Introduction to Amyotrophic Lateral Sclerosis and Exercise

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a fatal, progressive, degenerative motor neuron disease characterized by the aggregation of ubiquinated proteins in the affected motor neurons. There are three forms of ALS: “familial” (hereditary), “sporadic” (nonhereditary) and “ALS/dementia” (ALS that targets the brain). Sporadic ALS is the most common form of the disease (80-90 percent of all cases), and familial ALS occurs in about 5 percent of cases (Byrne et al., 2011). The cause of ALS is still not completely understood but has been linked to three primary genes: SOD1, encoding CuZn superoxide Dismutase (Rosen, 1993); ANG, encoding angiogenin (Conforti et al., 2008; Greenway et al. 2006; Paubel et al., 2008); and TARDP, encoding TAR DNA binding protein TDP-43 (Sreedharan et al., 2008). However, there are a variety of other genes suggested to cause ALS in some cases (Al-Chalabi et al., 2012; Kim et al., 2013).

ALS affects both upper and lower motor neurons. The motor neurons in the spinal cord, brain stem and cerebral motor cortex degenerate, resulting in a variety of signs and symptoms. The disease is characterized by the absence of sensory symptoms and findings.

Seventy percent of patients experience initial symptoms with leg, arm or bulbar (muscles used for swallowing) muscle focal weakness. Lower-extremity motor neuron clinical signs include muscle weakness, muscle atrophy, fasciculations (muscle twitches), hyperreflexia, hypotonicity and muscle cramps. Upper-extremity motor neuron clinical signs include spasticity, hyperreflexia and pathological reflexes. Bulbar signs include dysarthria, dysphagia (difficulty swallowing), sialorrhea (drooling) and pseudobulbar palsy (Dal Bellow-Haas et al., 1998). Cognition, extra-ocular eye movements and autonomic, bowel, bladder and sexual functions usually remain intact (Dal Bellow-Haas et al., 1998, Goldman & Bennett, 2000).

For a definite diagnosis of ALS, the body is divided into four regions:

1. bulbar – jaw, face, palate, larynx, and tongue;
2. cervical – neck, arm, hand, and diaphragm;
3. thoracic – back and abdomen; and
4. lumbosacral – back, abdomen, leg, and foot (Goldman & Bennett, 2000).

A definite diagnosis is made when upper and lower motor neuron signs are present in the bulbar region and two other spinal regions, or in three spinal regions. Individuals with motor neuron signs in only two spinal regions are classified as having probable ALS. Possible ALS is the diagnosis if dysfunction is present in only one region, or if a patient presents with only upper motor neuron signs in two regions, or if lower motor neuron signs are found in the upper-extremity muscles (Goldman & Bennett, 2000).

Muscle weakness progresses over time; the pattern and rate of deterioration vary widely. ALS has an incidence rate of two to four people in 100,000 (Goldman & Bennett, 2000). It is slightly more common in men than women, with the average age of onset in the mid-50s (Dal Bellow-Haas et al., 1998). The duration of the disease, from onset of symptoms until death, is 27 to 43 months; the average 5-year survival rate is 25 percent (Goldman & Bennett, 2000). However, about 10 percent of ALS patients survive for 10 or more years. Death is usually due to respiratory failure, which occurs approximately 3 years after symptoms from ALS are experienced (Shaw et al., 2001).

The cause of sporadic ALS is unknown. In a case study by Dal Bellow-Haas et al. (1998), a breakthrough in ALS research found that the disease may be caused by a mutation in the superoxide dismutase-1 (SOD1) gene. This would confirm studies by Bredesen et al., (1997); Bowling et al., (1993); and Kawamata, J. et al., (1997) that suggest that ALS is caused by free-radical injury.

Risk factors, such as head trauma, military deployment, excessive physical exertion, professional sports and chronic head trauma have been suggested to be linked with ALS; the majority of the literature has shown strong positive associations with only a few risk factors:

1. Exposure to hazardous chemicals / heavy metals
2. Oxidative stress
3. Smoking (for women only)

Pesticide exposure (Malek et al., 2012) and lead (D’ Amico et al., 2013) have been suggested to be linked with increased risk of ALS. However, the association is moderate and there are inconsistencies in the literature. Though the cause of oxidative stress is unknown, there is broad evidence that suggests oxidative damage detriments the pathogenesis of sporadic ALS (D’Amico et al., 2013). It is still unclear whether oxidative stress is a causal factor or a merely secondary effect of ALS. Vitamin and mineral intake may offer protective effects against the onset of ALS. A pooled analysis by Fitzgerald and colleagues (2013) examined the association between nutrient intake and risk of ALS from a compilation of 5 different studies, totaling 1,100,910 participants with ALS. Their findings suggested that consumption of foods high in carotenoids (carrots, sweet potatoes, spinach, kale, tomatoes, greens, etc.,) may aid in the prevention or delay of ALS. The authors did comment that their results were based solely on dietary intake and not supplementation (Freedman et al., 2013). Beta-carotene supplements have been associated with increased risk of cancer at different sites. Thus, current evidence suggests that an individual should not supplement beta-carotene, and instead focus on nutrients from their dietary intake.  Vitamin E has also been suggested to have similar protective effects against ALS (Wang et al., 2011; Michal Freedman et al, 2013), but further research is needed.

While the overall relationship between smoking and ALS appears weak (Alonso et al., 2010a), smoking has been strongly associated with ALS risk and poorer survival rates in women but not men (Alonso et al., 2010b).

Although severe depression is not a highly prevalent in persons with sporadic ALS (McElhiney et al., 2009), people who do experience psychological stress in the form of hopelessness, depression, and mental stress have shorter survival (McDonald et al., 1994). Positive moods are associated with longer durations of survival (6 months) (Johnston et al., 1999). It is possible that psychological stressors contribute to the biological changes, such as oxidative stress, that enhance the onset and progression of ALS. Though, more longitudinal studies must be conducted to solidify these findings.

Evaluation of Aerobic Capacity and Strength

Methods for the evaluation of strength in people with ALS include a clinical neurological exam, manual muscle testing (MMT) and rating scales. These methods are subjective and lack sensitivity to detect small changes (Agre, Magness, Hull, Wright, Baxter, Patterson & Stradel, 1987; Andres, Hedlund, Finison, Conlon, Felmus & Munsat, 1986; Goonetilleke, Modares-Sadeghi, & Guiloff, 1994; Wiles & Karni, 1983). Strength depends on many factors, including the type of contraction, speed of contraction, length-tension relationship, neuronal discharge, cross-sectional area of muscle and motivation (Andres et al., 1986).

Tourtellotte et al. (cited in Andres et al., 1986) developed a quantitative measurement system to evaluate multiple sclerosis that uses measured date rather than grading scales. Andres et al. (1986) developed a similar set of standardized tests for people with ALS. The test, the Tufts Quantitative Neuromuscular Exam (TQNE), possesses the following features:

1. quantitative scores generate interval data;
2. low test-retest variation;
3. records both mild and severe impairment accurately;
4. measures both upper and lower motor neuron functions;
5. assesses different levels of the neuraxis;
6. is time-efficient;
7. is inexpensive;
8. is sensitive to small changes;
9. is easy to learn for both the examiner and patient;
10. can be computer-stored and analyzed; and
11. is suitable for multi-institutional studies (Andres et al., 1986).

The four sections of the test are pulmonary function, oropharyngeal, timed motor activities and maximal isometric strength. Pulmonary function tests measure forced vital capacity and maximum voluntary ventilation; oropharyngeal measures diadochokinetic syllable production; timed motor activities measure the dexterity of each hand and speed of walking 15 feet; and maximal isometric strength tests isometric force of nine muscle groups bilaterally and hand grip strength.

The TQNE reduces the error of the isometric strength testing due to positioning, patient instruction, verbal encouragement, muscle contraction/relaxation time and stabilization (Andres et al., 1986). Directing quantitative measurement of spasticity is still a problem. The timed walking and timed hand activities may indirectly give evidence of the degree of spasticity (Andres et al., 1986).

In a study by Wiles and Karni (1983), the measurement of the strength of a maximum voluntary contraction is the simplest and most direct means of assessing the amount of active muscle in a particular group. In a disease, this contraction is reduced due to the amount of contractile material or activation impairment, or both. They found that in muscle disease, the maximum voluntary contraction reflects the amount of functioning contractile muscle, assuming normal excitation processes. With a disease of the central or peripheral nervous system, strength changes reflect altered excitation processes, and muscle mass is secondary. In this study, they claim that these uncertainties can be overcome by always performing the measurements in the same manner following an established routine, but this is probably not the best method to determine strength in a person with ALS.

Studies by Agre et al. (1987) and Goonetilleke et al. (1994) examined the reliability, accuracy, reproducibility and variability of hand-held dynamometry in the assessment of both upper- and lower-extremity strength. The study by Goonetilleke et al. (1994) was specific to motor neuron disease. Variability is high when using dynamometry to measure lower-extremity strength; dynamometry is better used for upper-extremity strength measurement (Agre et al., 1987). Goonetilleke et al. (1994) determined that there was no difference in variability when reporting the results of three trials on handgrip strength. Variability did not change with reporting the highest value, the mean or the median. The mean is prone to the effects of abnormally high or low readings in one assessment due to fatigue, but there was still no difference in variability. To assess handgrip strength in people with ALS, the mean should be reported, due to fatigue causing possible differences.

Lower free fatty acids (FFA), ketones and esterified carnitine in the plasma during exercise and 90 minutes post-exercise were observed in the people with ALS. The lower plasma FFA may indicate increased FFA mobilization from adipose tissue. A conclusion drawn from this study is that patients with ALS exhibit specific abnormal physiologic and metabolic responses to exercise (Sanjak et al, 1987). This includes decreased work capacity, increased oxygen cost of submaximal exercise, and abnormalities in plasma and muscle lipid metabolism. It is important to note that these abnormalities did not prevent the patients with ALS from performing prolonged exercise. Specific delineation of all abnormalities in energy production and substrate utilization is an important prerequisite for the clinician and exercise specialist in planning a safe and adequate exercise program (Sanjak et al., 1987).

Wright, Kilmer, McCrory, Aitkens, Holcomb & Bernauer (1996) studied the effects of a 12-week walking program on people with progressive neuromuscular disease. The purpose of the study was to determine the effects of aerobic training in this population, and whether patients would adhere to a self-monitored, home-based exercise program. This study showed moderate-intensity aerobic walking three to four days per week safely produced improvements in work capacity, aerobic capacity and cardiovascular variables such as decreased heart rate and blood pressure (Wright et al., 1996). Improvement in physical fitness can potentially reduce the strains of daily living by increasing reserve capacities. This would allow individuals to meet the physiological demands required for activities of daily living (ADL) more effectively (Wright et al., 1996). This program was safe and well adhered-to by participants in this study.

A physiological change in people with ALS is an elevated creatine phosphokinase level (CPK). Creatine phosphokinase is an enzyme that is usually in high concentration in muscle tissue to meet the energy demands of the contracting muscle. It is usually elevated in inflammatory and degenerative muscle disease, but normal in neuropathic diseases (DeLisa & Tipton, 1979). CPK levels are elevated in 50 to 7 percent of the patients with motor neuron diseases, especially ALS (DeLisa & Tipton, 1979); these levels are usually five to six times above normal, but depend on the activity level of the person. (CPK is an intracellular enzyme. As ALS progresses, cells degenerate and rupture, releasing CPK into the blood stream, thus elevating serum levels.) DeLisa and Tipton (1979) found that bed rest will decrease CPK levels, but that moderate exercise will increase the levels. This is normal, even in a healthy population. What is abnormal is that the CPK levels do not return to a normal level even after 24-hour bed rest. As muscle mass decreases with progression of the disease, CPK values return to normal limits.

Exercise Testing and Prescription

Sinaki and Mulder (cited in Dal Bellow-Haas et al., 1998) describe the natural course of ALS as six stages:

• Stage I: Early stage of the disease. Independent in mobility and ADL. A specific group of muscles are mildly weak; may be limitations in performance, endurance, or both.
• Stage II: Moderate weakness in groups of muscles.
• Stage III: Still ambulatory but has severe weakness in certain muscle groups. May exhibit mild to moderate limitation of function. May have difficulty holding head erect.
• Stage IV: Severe weakness of the legs and mild involvement of the arms. May use a wheelchair and may be unable to perform ADL.
• Stage V: Progressive weakness and deterioration of mobility and endurance. Uses a wheelchair. Arm muscles may exhibit moderate or severe weakness. May exhibit pain in immobilized joints.
• Stage VI: Bedridden and requires maximal assistance with ADL. Progressive respiratory distress develops.

The key to exercise testing and prescription is determination of the stage of the disease. Regardless of the stage, care must be taken to prevent overuse fatigue and disuse atrophy (Dal Bellow-Haas et al., 1998). The four exercise program functions are planning, implementation, documentation, and feedback/program modification (Smith, 2000). In the planning stage, attentiveness in collecting and assessing information, obtaining physical assessments, and setting realistic goals is important. While functional gains as a result of exercise have not yet been determined, exercise may be physiologically and psychologically beneficial for patients with ALS (Dal Bellow-Haas et al., 1998). Strengthening and flexibility should also be included as part of the program.

The initial assessment can be done following the TQNE described in the study by Andres et al. (Andres et al., 1986). Timed tests include speech rate, phone dialing and pegboard test for hand dexterity, and a 15-foot walk. Isometric strength testing includes shoulder flexion/extension, elbow flexion/extension, hip flexion/extension, knee flexion/extension, and dorsi/plantar flexion (Andres et al., 1986). The strength of the head extensors should also be tested due to head drop developing as the disease progresses. Active range of motion and flexibility of each joint should also be measured. Sanjak and colleagues (1987) found that graded exercise cycling in 35 participants with ALS was able to stimulate linear responses in oxygen consumption and heart rate, indicating that modified aerobic tests are feasible in this population. As long as the patient is able, a submaximal recumbent cycle, all-extremity ergometer, or bike test may be performed to estimate aerobic capacity. Caution should be taken if maximal aerobic capacity is to be assessed, as high-intensity exercise may promote dangerous oxidative stress in people with ALS. If the participant is ambulatory, a more feasible method of measuring endurance would be through a six-minute walk test (6MWT). The ALS functional rating scale can also be administered to the patient. The patient rates his or her functional status (Dal Bellow-Haas et al., 1998). A list of medications, dosages, and administering times should also be requested from the patient.

Once the assessment is complete, an exercise program can be designed. When designing the program, factors to be considered include scheduling, exercise selection, and exercise intensity and duration. Aerobic conditioning should be performed three days per week, alternating days. Muscular strength and endurance work can be performed on the same day as long as fatigue and overuse are not an issue. The patient needs to be able to maintain ADL. Range of motion, stretching, balance, and gait exercises can be performed on alternate days. The goals of the program are based on the needs of the patient, but the desire to maintain function and prolong ability as long as possible are probably the most important (Smith, 2000).

The walking program outlined in the study by Wright et al. (1996) would be well-suited for individuals with ALS, depending on the stage of the disease. The target heart rate is determined by the Karvonen method, and exercise intensity is established between 50 and 60 percent of target heart rate range. Progression of the walking program is gradual. The first two weeks consist of walking 15 minutes, three times per week. At week three, the time is increased to 20 to 30 minutes. As long as the person is able to maintain balance, this would be an excellent program for someone in the initial stages of the disease. If balance is a problem, a recumbent bicycle could be used with the same operating parameters.

With strength training, it is best to be conservative. One set of 10 repetitions is sufficient for a strengthening program. A 30-minute full body stretching and both active and passive range of motion exercises are included. Respiratory distress is an inevitable complication of the disease; deep breathing exercises should be performed on the same days as flexibility training. It is important to know the effects of the medications. When medications were taken, and changes made to medication types and dosages may affect the exercise program. Maintaining communication with the physician through the patient is crucial.

Documentation is important. It should include exercise date, time, exercise performed, duration and intensity, what medications were taken and when, resting heart rate, blood pressure, previous exercise that day or ADL, changes to the program or changes with the patient, and any notes of conversations with the physician or other medical personnel.

Working with a person who has ALS is more than just providing instruction for exercise. Through exercise, goal-setting and treatment planning, patients may gain some sense of control over what is happening to their bodies, enabling them to better cope with functional losses.

More time will need to be spent with a patient with ALS when performing an exercise program. Periodic changes will occur, with assessments being done weekly or even daily. As the disease progress, more and more time will need to be spent with the person (Smith, 2000).

1. An acquired disease is one that is not inherited.
2. A disturbance of articulation due to emotional stress, brain injury, or paralysis, incoordination, or spasticity of the muscles used for speaking.
3. Creatine phosphokinase is the enzyme that catalyzes the transfer of a phosphate from creatinephospate (CP) to ADP to produce ATP. This enzyme is critical to muscle contraction.

Benefits of Exercise

Since oxidative stress worsens ALS progression, researchers have suggested that intense physical activity may exacerbate oxidative damage. Though, continuing evidence in recent years has suggested that moderate physical activity is beneficial for this population (de Almeida et al., 2012). Flexibility exercise can improve range of motion and reduce muscle tightness and should be prescribed to all persons with ALS (de Carvalho et al., 1999). Cardiovascular exercise (moderate intensity) for people with ALS has been suggested to delay the progression of respiratory failure (Pinto et al., 1999). Sparse literature has also found minor gains in respiratory impairment (Cheah et al., 2009). When comparing a running and swimming program in mice with ALS, Deforges and colleagues (2009) found that swimming training had benefits associated with disease progression, weight control, motor function, and was able to increase the lifespans of the mice by 20 percent. Another study by (Drory et al., 2001) and colleagues demonstrated that a regular home-based exercise program of moderate intensity, slowed the deterioration on the ALS functional rating scale, which is similar to results found from moderate-intensity resistance exercise alone (Aitkens et al., 1993). Exercise may delay disease progression, promote weight control, preserve motor function, and improve the quality of life in persons with ALS. Clinical interventions are needed to examine the effects of exercise on physiological outcomes and quality of life in persons with ALS, to develop suitable exercise guidelines.

It is important to note that, physical activity involves motor neuron activation, which invokes oxidative stress. This, increase in free radical production and glutamate is usually regulated by homeostasis of the body, but does not occur in persons with ALS with a high risk of developing neurotoxicity (Chen et al., 2008; Dalbello et al., 2008). More research is needed to determine which exercises are beneficial or harmful to persons with ALS. With the current knowledge at hand, it may be best to prescribe no higher than moderate-intensity exercise to persons with ALS. There are currently trials underway, such as the FACTS-2-ALS trial, which may change our understanding of exercise and ALS in the near future.

Conclusion

ALS is a fatal, progressive degenerative motor neuron disease that affects the upper and lower motor neurons, which results in muscle weakness. Though ALS is idiopathic, there are a number of risk factors associated with an increased onset and progression of the disease, which include: oxidative stress, smoking in women and exposure to hazardous chemicals and metals. A positive mood, combined with safe physical activity and a balanced diet, may prolong the lifespan of people with ALS. When designing an exercise program, it is important to assess the current stage of ALS and the physical status of the individual. Some researchers have suggested that physical activity is detrimental for disease progression. However, evidence appears to support the prescription of moderate-intensity exercise towards people in the early-stages of ALS. More research is needed to establish appropriate exercise guidelines and assess the impact that exercise has on the quality of life in people with various stages of ALS.