The Evaluation and Management of Fatigue

Aaron B. Holley, MD


October 14, 2015

What Is Fatigue?

The Annals of Internal Medicine recently published two systematic reviews on the diagnosis and treatment of the chronic fatigue syndrome (CFS).[1,2] The reviews use the term "myalgic encephalomyelitis/chronic fatigue syndrome" (ME/CFS) to define this condition, and as the accompanying editorial points out,[3] an expert panel convened by the Institute of Medicine (IOM) recently found that ME/CFS is a disease with a physiologic basis.[4] It is not a purely psychological problem.

As a sleep physician, I am often asked to evaluate patients with a complaint of fatigue—which raises the question, how does a physician differentiate ME/CFS from other common causes of fatigue? Regardless of etiology, how do we manage fatigue?

Any discussion of fatigue must begin by defining the term. Max Hirshkowitz, PhD, a professor and renowned sleep researcher at Baylor College of Medicine, provided a complete definition that will serve as a reference for the remainder of this review.[5] He stressed the following points:

  1. Fatigue is perceived as a sense of tiredness, exhaustion, or lack of energy.

  2. Fatigue that is nonpathologic will improve with rest.

  3. Fatigue can be provoked by exceeding capacity in terms of time-on-task or stress load.

  4. Stress load can be altered by external (environmental) or internal (genetic predisposition, medical or behavioral illness) factors.

  5. Sleep duration, quality, and timing are significant mediators of the manifestations of fatigue.

In a global sense, then, fatigue occurs when circumstances require some combination of physical and cognitive work that exceeds the capacity of the individual. The point at which this will occur varies by genetics, training, and sleep.

Diagnostic Challenges

There is value in characterizing the patient's fatigue complaint. Sleep physicians attempt to do this for a living, and it's a messy business at best. Some will use the term "fatigue" to describe sleepiness, whereas others will not. It is often equated with a central perception, including "lack of energy," "no motivation," "difficulty concentrating," or a perceived deficit in some other aspect of executive function.

Still other patients are using the term "fatigue" to mean exercise intolerance or the inability to push through a difficult workday. Oftentimes, the patient comes to physician attention owing to poor performance in a particular setting—such as on the job, in the classroom, or on the playing field. Clarifying the circumstances under which the perception of fatigue becomes a problem is critical to identifying the cause and designing the mitigation strategy.[5,6]

An appropriate review of the possible contributors to fatigue is also important. Because sleep plays such a pivotal role, a proper sleep history is mandatory. Any discussion of sleep disorders should start with a review of total sleep time. Current data show that cognitive, behavioral, and metabolic changes consistently occur with chronic sleep restriction to less than 6 hours per night.[7,8,9]

We also know that an increasing percentage of the population averages less than 6 hours of sleep per night.[10,11] The average adult does not optimize cognitive, behavioral, and metabolic functions unless they're sleeping for more than 7 hours per night.[8] In short, insufficient sleep should be suspected as a contributor when a patient complains of fatigue.

Circadian misalignment, even with sufficient sleep, also leads to fatigue and performance decrements. There is the obvious case of people who do shift work, but circadian misalignment can also affect evening types who are forced to work early (slight sleep phase delay), or morning types who are forced to work late (slight sleep phase advance); the former more commonly suffer from fatigue and performance deficits.

Any patient who complains of fatigue and does shift work, particularly night shift or work with frequent shift changes, should be evaluated for shift-worker disorder. Persons who do night-shift work are known to average less sleep per 24-hour period than day-shift workers, and by definition they will have circadian misalignment.[12]

Sleep disorders, such as insomnia and obstructive sleep apnea syndrome (OSAS), are also common. Insomnia can contribute to fatigue[13] and can also be caused by such disorders as ME/CFS or overtraining syndrome (OTS),[14,15] so the temporal relationship between the insomnia and the onset of fatigue must be fleshed out. OSAS is very common and easy to diagnose, but quantifying its effect on fatigue can be difficult, particularly when the disease is mild.[16,17] Unfortunately, compliance with treatment is poor.[18]

Fatigue as defined by Dr Hirshkowitz focuses heavily on stress and workload; although these may be difficult to quantify, an assessment of current cognitive and physical loads is an important part of a fatigue evaluation. Most physicians can easily understand how a high physical workload can result in fatigue. However, studies of overreaching (OR) or OTS in athletes have shown that the likelihood of developing fatigue is governed by the complex interaction between physical, occupational, and psychosocial factors.[14,15]

Working at a military hospital outside Washington, DC, I see few patients with physical workloads that approach the level of a competitive athlete. I do see many patients who must meet physical fitness standards every 6 months and who otherwise have high levels of occupational and cognitive stress load, and long commutes that restrict total sleep time. This combination of stressors can easily lead to both central and peripheral fatigue syndromes. Because workload is often related to occupation, many patients will have difficulty making changes. However, mitigation strategies can be implemented within the confines of a rigid work schedule.[19]

Differentiating ME/CFS from fatigue due to more common causes will be difficult. To begin with the definition of ME/CFS is nebulous. The Annals of Internal Medicine systematic review noted that eight case definitions have been used in the literature to define ME/CFS; the new case definition presented by the IOM is the ninth case definition proposed.[1] In general, studies that evaluated the different case definitions recruited patients from specialty clinics and compared them with asymptomatic controls.

Some studies were more inclusive than others, and most required that alternative causes of fatigue be excluded. In clinical practice, we need to be able to distinguish patients with ME/CFS from those with fatigue from other causes, so it's unclear whether these scores will be helpful when we evaluate our patients. Symptoms were more severe in patients defined as having ME or ME/CFS than in those with CFS alone. In addition, the reference standard used to establish the diagnosis was not standardized, so comparisons across studies is difficult.[1]

Summarizing the Diagnostic Criteria

The editorial accompanying the systematic reviews on ME/CFS summarizes the criteria for diagnosis well.[3] I will paraphrase.

The patient must have each of three symptoms:

  • Profound impairment in normal activities for at least 6 months, not alleviated by rest;

  • Postexertional malaise; and

  • Unrefreshing sleep.

At least one of the following two symptoms is also required:

As stated in the preceding paragraph, the data compiled for the systematic reviews was limited, and this definition does not substantially differ from many of those previously used. Still, there are several practical points to be made here.

First, although prevalence rates vary by definition, estimates range between 0.3% and 2.5% of the population.[1] One could therefore argue that ME/CFS is not as rare as we think (or as I thought), so it should be considered during a fatigue evaluation.

Second, properly characterizing fatigue will require a very thorough history. Time course and contributing factors are critical. Clinics that frequently manage fatigue complaints would be well-served by designing questionnaires to be filled out before appointments, lest they attempt to fit a 60-minute history into a 15-minute appointment slot.

Finally, there is considerable overlap with other causes of fatigue, such as OTS and OR—both of which have been associated with postexertional malaise, cognitive impairment, respiratory infections, orthostatic changes, and unrefreshing sleep.

Fatigue Mitigation

Although both OTS and OR should improve with rest (whereas ME/CFS will not), with OTS in particular, it may take months before the patient feels better. In many cases, the true cause of fatigue will only be apparent with response to rest over a period of many months.

Fatigue mitigation strategies will vary by individual and type of fatigue. In keeping with the discussion above, addressing identified sleep-related contributions is critical. There are recognized, effective treatments for OSAS, insomnia, and insufficient sleep syndrome. All involve behavior changes that some will perceive as difficult, and outcomes will depend on adherence.

Treatment for circadian misalignment often involves occupational changes that may be hard if they affect career progression. Finally, OTS and OR will require rest. This means a reduction in or complete cessation of associated training, along with relief from social or occupational stressors.[14,15]

In addition to behavior changes for circadian misalignment, sleep efficiency, and total sleep time, there are appropriate medications for fatigue mitigation. Caffeine is the most frequently used stimulant worldwide. It has proven effects on cognitive function and is safe to use in moderate doses (100-400 mg/day).[20,21]

Modafinil, armodafinil, and amphetamine-based medications also have proven wakefulness-promoting and cognitive effects.[21] It is important to note that none of these medications should be thought of as a substitute for sleep. They help with executive function and promote wakefulness, but do nothing to restore physiology otherwise. They can be used as mitigating agents, but none are considered a treatment per se for ME/CFS, OTS, or sleep-related disease.

The ME/CFS treatment review synthesized data from a total of 35 trials in 45 publications. Most trials were small and of fair to poor quality. Outcome measures varied, so comparisons across studies could not be made. They found some evidence for benefit for counseling and graded exercise therapies. Several different types of counseling and graded exercise therapies were studied, and no one form of therapy was considered better than another. Trials of an immune-modulator called rintatolimod, an intravenously delivered medication that is not approved by the US Food and Drug Administration for any indication at this time, also suggested benefit.[2]

In summary, fatigue is a common patient complaint. ME/CFS has a prevalence of 0.3%-2.5%, and should be considered as a possible cause for fatigue. It is difficult to distinguish ME/CFS from other common causes, and to an extent, it will be a diagnosis of exclusion.

There are countless medical, behavioral, and psychological causes of fatigue that are unrelated to ME/CFS but share similar characteristics with this syndrome. A comprehensive history and medical evaluation is important, and a trial of rest and removal from significant stressors is needed for proper diagnosis and treatment. More research on diagnostic criteria and therapy is needed, but the recent Annals of Internal Medicine and IOM reports highlight the importance of recognizing this disabling disease.


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