Fatigue and Exercise Intolerance

Among the most common symptoms of disorders of energy metabolism is exercise intolerance, resulting in reduced stamina often associated with symptoms of pain and/or fatigue and/or heaviness in the active muscle groups.

The ability to exercise depends on a number of factors (Flaherty, 2001):

  1. Adequate delivery of oxygen and nutrients to the muscle
  2. The ability of the muscle to utilize oxygen
  3. The ability of the muscle to utilize and metabolize nutrients
  4. The ability of the muscle to generate adequate energy

Individuals with mitochondrial disease have limited exercise capacity because of an inability to fully extract and use oxygen (Jeppesen, 2006), resulting in a limited ability to generate energy for normal activity. The high number of mitochondrial mutations in skeletal muscle suggests that mitochondrial disease patients are prone to having exercise intolerance (Jeppesen, 2006).

Patients also describe a more global fatigue that goes beyond the muscles, and is often associated with a slowing in thinking, diminished responsiveness or lethargy, confusion, or in some, an unmasking of behaviors normally under control. There is great overlap between the symptoms of exercise intolerance and generalized fatigue. Because these often run together and it is not easily possible to distinguish whether the fatigue is limited to just the muscle or whether it is a wider issue, these topics are discussed together here.

Fatigue and Exercise Intolerance

Mitochondrial patients are not necessarily always weak or tired. Patients might be able to muster adequate energy for periods of time but it is usually short-lived and they tire quickly, not unlike a battery that discharges too rapidly. Affected children fatigue easily on the playground relative to their peers and siblings, and may tend to drift toward more sedentary activities. A period of rest or sleep is generally required before energy levels are restored. Following rest a patient may demonstrate apparently normal stamina and a clinician will not detect weakness on examination (which differentiates many of these patients from those with primary muscular dystrophies).

Impaired oxidative phosphorylation not only causes muscle fatigue but also muscle cramping with or without tenderness, or a feeling of extreme heaviness in the muscles. These symptoms are especially severe in those muscle groups being used, and patients often complain of discomfort in the legs or even muscle spasms. The discomfort may be felt immediately following the activity or later on, waking up the patient from sleep. Following more prolonged or intensive activity, the pain or heaviness can persist into the next day(s) despite rest. A subset of patients has pain associated with elevations of CK and intensive exercise can lead to frank myoglobinuria; there may also be associated lactic acidemia (DiMauro, 1999).

Exercise intolerance is not restricted to the large muscle groups in the body but can also involve the small muscles. Writing can be a challenge; too much writing leads to fatigue and/or cramping or spasms. The quality of penmanship can be observed to deteriorate over the course of a writing assignment with letter formation becoming more erratic and messy. The tachypnea that goes with exercise may be exaggerated and could be due in part to respiratory muscle fatigue in the chest wall and diaphragm. An excessive tachycardia may occur due to increased ventilation and cardiac output during exercise. (Testa, 2005). The blurring of vision with or without strabismus and/or ptosis may reflect eye muscle fatigue. Finally, oral muscle weakness may lead to an active avoidance of foods that demand a lot of chewing (such as beef or chicken) and a preference for softer, mushier foods and/or liquids. In adequate intake can result in a drop in calories as patients tire with eating.

In the past, individuals with mitochondrial disease were advised to avoid physical activity because of concern about exhaustion and cellular muscle damage leading to potential lactic acidosis and myoglobinuria. Avoidance of activity deconditions the muscles, aggravating the exercise intolerance. Aerobic training can improve oxidative capacity and quality of life (Jeppensen, 2006). Endurance exercise training can improve exercise tolerance by increasing cardiac output, mitochondrial density, muscle vascularization, and raising enzymatic activity. This leads to improvement of oxidative phosphorylation and antioxidant capacity. There is also evidence that resistance exercise training also improves skeletal muscle functions by increasing mitochondrial function within the cell (Mahoney, 2002).

Debilitating fatigue can occur with infectious illnesses, may outlast th other symptoms of the infection, and the recovery time can be very prolonged (see FEVER AND INFECTION).

An underappreciated component of fatigue is emotional distress, i.e., significant or prolonged anxiety or depression, often present as a result of the chronic, progressive, and unpredictable nature of the disease. Unlike physical exertion which one can halt to reduce quickly energy expenditures, psychological stress is harder to control and energy losses can be significant and persistent. Just because a patient is anxious or depressed, respectful caution is needed to avoid "blaming" a patient's entire phenotype on his/her psychological state. However, it can be a contributor to the patient's overall state of fatigue.

Patients with mitochondrial disease may have significant autonomic dysfunction (Zelnik, 1996; Axelrod, 2006) including vascular dysautonomia characterized by tachy- and bradycardia, dizziness, and orthostatic changes in heart rate and blood pressure. Those factors that aggravate autonomic dysfunction can precipitate headaches and significant fatigue. Other signs of autonomic dysfunction include heat or cold intolerance, unusual sweating patterns, spontaneous pallor/flushing/mottling without cause, or abnormal gut motility or bladder function. Those with heat or cold intolerance can show become very tired when exposed to extremes in temperature or with climate changes, especially in the spring when the weather warms. However, the weather is sometimes blamed when (unrelated) environmental allergies are the more significant issue, especially since both become issues around the same time (e.g., spring time).

Patients with energy disorders are at risk for developing obstructive and central sleep apnea. Such disturbances in sleep can reduce the quality of sleep, leaving patients with significant day-time fatigue.

Finally, patients with cardiac disease or advanced kidney or liver disease related to their underlying disease can manifest fatigue. Anemia when present is another etiology.

Mitochondrial Differential Diagnosis

  1. Mitochondrial disease
  2. Muscle deconditioning
  3. Excessive physical exertion
  4. Infection or (prolonged) recovery from an infections illness
  5. Emotional distress / mental health issues
  6. Excessive ambient heat/humidity or cold
  7. Autonomic dysregulation
  8. Sleep disturbance (obstructive or central sleep apnea)
  9. Other organ involvement -
    1. Cardiac
    2. Liver
    3. Kidney
    4. Anemia
  10. Other unrelated causes - environmental or food allergies

Assessment and Recommendations

1. Muscle deconditioning or excessive physical exertion:

a. Determine what symptoms are associated with the fatigue and whether or not there are any trigger factors - physical exertion, writing, chewing, temperature exposure or weather changes.

b. Is the patient reasonably active physically?

c. Does the patient become short of breath unexpectedly while awake? Could there be an issue with respiratory muscle or diaphragmatic weakness?

d. Is there a history of myoglobinuria?

Recommendations:

1. Regarding exercise -

a. Ensure a routine that allows regular rest periods during the day and which is flexible to accommodate a patient's high-energy and lower-energy days ("good days" and "bad days"). Adequate time must be allowed for patients to rest up in preparation for a higher-energy activity or situation.

b. Older children and adolescents need to be educated to "listen to their bodies" so that they learn to pace themselves during activity. This means taking regular rests, resulting in being more productive and staying longer at an enjoyable activity. Parents need to impose a structure on younger children during playtime. Some children regulate their own level of activity so this is less of a concern.

c. Ideally, based on personal experience, a child will learn when to stop in advance of developing uncomfortable symptoms. As can be expected, adolescents may "test their limits" but this can be a useful learning opportunity if they learn from the experience and adjust their behavior accordingly.

d. Some patients spend so many days feeling under the weather that they "overdo it" when they wake feeling well; this of course results in days of feeling unwell again. A more measured return to activity may prove more beneficial in the long run.

e. Supervised endurance and/or resistance training can allow a gradual increase in activity (Mahoney, 2002). Exercise therapists or personal trainers may be able to craft a reasonable and safe exercise protocol.

f. When indicated, physical therapy can be a beneficial treatment modality. However, the therapist should not set goals that are more appropriate for a post-surgical patient who is recovering from surgery and who can be expected to reach a normal stamina level. A gradual increase in stamina is a more reasonable goal with emphasis on flexibility, balance and coordination, and muscle tone. There is no benefit to be gained by pushing a mitochondrial patient to the point of exhaustion.

2. Referral to a pulmonologist when there is a history of dyspnea at rest.

3. If there is a history of intermittent frankly dark-colored urine (suggesting the possibility of myoglobinuria):

a. The following tests should be performed when symptoms are present - CPK in blood, and urinalysis and urine myoglobin.

b. If myoglobinuria is confirmed, the patient and family should be counseled about the need for assessment and management (fluids, dextrose, urine alkalinization) when rhabdomyolysis occurs.

2. Infection or (prolonged) recovery from an infectious illness

a. History of recent infection or infectious symptoms?

Recommendations:

1. CBC and WBC differential count, cultures, as appropriate.

2. Treat infections aggressively. See INFECTIONS.

3. Emotional distress / mental health issues

a. Is there a psychological component to the patient's fatigue?

Recommendations:

1. Referral for psychological evaluation and/or psychotherapy as appropriate.

2. See PSYCHIATRIC-BEHAVIORAL ISSUES

4. Excessive ambient heat/humidity or cold:

a. Are the patient's symptoms related to temperature?

Recommendations:

1. If the patient's fatigue is related to temperature (excessive cold or heat), patients or their caregivers should monitor the ambient temperature and take appropriate precautions. Some cannot tolerate being outside in the summer beyond a few minutes unless they are in water (and sometimes even then for limited periods of time because they become chilled if the water temperature is too cold). Air-conditioning might be needed at home or in the classroom/work-place to keep temperatures within a comfortable range.

5. Autonomic dysregulation:

a. Assess for autonomic dysfunction and those factors that can cause autonomic dysfunction: temperature dysregulation, abnormal (usually low) basal body temperature, heat and cold intolerance, abnormal sweating patterns, tachy- and bradycardia, dizziness, and bladder dysfunction.

Recommendations:

1. Evaluate for vascular dysautonomia, and look for orthostatic changes in heart rate and blood pressure which can cause fatigue and dizziness.

2. If fluid or calorie intake is low, encourage fluids and/or calories. A trial of IV fluids might improve symptoms and support an autonomic etiology.

3. See AUTONOMIC DYSREGULATION.

6. Sleep disturbance (obstructive or central sleep apnea:

a. What is the patient's best time of day… after waking up in the morning? If not, could there be an issue with obstructive sleep apnea? Ask about snoring or restlessness during sleep, morning exhaustion, or day-time napping.

Recommendations:

1. Refer for a sleep evaluation.

7. Cardiac cause:

a. Check for other symptoms of heart disease.

Recommendations:

1. Chest x-ray and EKG

2. Refer to the ER or to a cardiologist depending on the urgency of the situation.

8. Liver cause:

a. Check for other symptoms of liver disease.

Recommendations:

1. Liver functions

2. Refer to a gastroenterologist.

9. Renal cause:

a. Check for other symptoms of renal disease.

Recommendations:

1. BUN, creatinine, urinalysis

2. See RENAL/BLADDER.

3. Refer to a nephrologist.

10. Anemia as a cause:

a. Check for other symptoms of anemia.

Recommendations:

1. CBC, differential, platelets.

2. See HEMATOLOGIC.

3. Refer to a hematologist.

11. Unrelated causes:

a. Check for other symptoms of allergies (environmental or food).

Recommendations:

1. Assess as appropriate.

References

Axelrod FB, Chelimsky G, Weese-Mayer DE. Pediatric autonomic disorders. Pediatrics 2006;118:309-21.

DiMauro S. Exercise intolerance and the mitochondrial respiratory chain. Ital J Neurol Sci 1999:20:387-93.

Flaherty KR, Wald J, Weisman IM, et al. Unexplained exertional limitation: Characterization of patients with a mitochondrial myopathy. Am J Resp Crit Care Med 2001;164(3):425-32.

Jeppesen TD, Schwartz M, Olsen DB, et al. Aerobic training is safe and improves exercise capacity in patients with mitochondrial myopathy. Brain 2006;129(Pt12):3402-12.

Mahoney D, Parise G, Tarnopolsky MA. Nutritional and exercise-based therapies in the treatment of mitochondrial disease. Curr Opin Clin Nutr Metab Care 2002;5(6):619-29.

Testa M, Navazio FM, Neugebauer J. Recognition, diagnosis, and treatment of mitochondrial myopathies in endurance athletes. Curr Sports Med Rep 2005;4(5):282-7.

Zelnik N, Axelrod FB, Leschinsky E, et al. Mitochondrial encephalomyopathies presenting with features of autonomic and visceral dysfunction. Pediatr Neurol 1996;14:251-4.

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