Diagnosing CFS can be challenging for health care professionals for many reasons; the most important one is finding fatigue in a large number of illnesses and disorders. We reviewed information available about evaluation of chronic fatigue and discuss it in 3 parts: history, exam, and diagnostic tests.
History and Differentials
Because CFS is a diagnosis of exclusion,1 a full detailed history is considered essential. The history should include a detailed account of the symptoms, the associated disability, the choice of coping strategies, and importantly, the patient's own understanding of his/her illness.65 Every patient should be carefully evaluated for certain medical, psychiatric, and neurologic diseases that can cause fatigue as the most prominent symptom (Table 3). Two of the important differential diagnoses are depression and fibromyalgia. Although it is difficult to differentiate CFS from fibromyalgia confidently depending on the history or other reported differences of cognitive dysfunction components or clinical pain measures,66,67 CFS and fibromyalgia commonly co-occur within the concept of central sensitivity syndromes or functional somatic syndromes.68 This co-occurring increases functional impairment when compared to CFS individuals alone.69,70 Some of the distinguishing features between CFS and fibromyalgia include evidence for triggering viral infection and lower level of serum acylcarnitine observed in CFS patients, which is lacking in the majority of patients with fibromyalgia;71 slower information-processing in CFS patients compared to impaired control of attention in fibromyalgia patients;66 and lacking of the characteristic diffuse soft tissue pain and pain on palpation in at least 11 of 18 paired tender points in CFS patients.
Chronic Fatigue Syndrome Differential Diagnoses
Every CFS evaluation should include a mental status examination to identify abnormalities in mood, intellectual function, memory, and personality. Particular attention should be directed toward current symptoms of depressive, anxious, self-destructive thoughts and observable signs such as psychomotor retardation.1 Although there is no definite physical finding, a full and thorough physical examination may be helpful in excluding other conditions. Multiple studies have suggested dysautonomia with greater increase in heart rate together with a more pronounced systolic blood pressure fall on standing in CFS patients compared to healthy individuals.46,72 Other studies found no statistically significant differences in either heart rate or galvanic skin resistance both during a normal day and before, during, and after exercise testing.73
The CDC has recommended the following initial screening tests when evaluating patients with CFS: urinalysis, total protein, glucose, C-reactive protein, phosphorus, electrolyte, complete blood count with leukocyte differential, alkaline phosphatase, creatinine, blood urea nitrogen, albumin, antinuclear antibody and rheumatoid factor, globulin, calcium, alanine aminotransferase or aspartate transaminase serum level, and thyroid function tests (thyroid stimulating hormone and free T4).1 Further tests or referral to specialists may be indicated to confirm or exclude a diagnosis that better explains the fatigue state or to follow up on results of the initial screening tests.
Multiple other studies have tried to find biomarkers or radiological markers for CFS. Erythrocyte sedimentation rate was normal in all 23 CFS patients in one study.74 Another study found that concentrations of C-reactive protein, β2-microglobulin, and neopterin were higher in patients with CFS (p ≤ .01).75 On the other hand, a study by Swanink et al.76 found that complete blood cell count, serum chemistry panel, C-reactive protein, and serologic tests were not different in 88 patients with CFS when compared to a control group. A potential role for DHEA in CFS, both therapeutically and as a diagnostic tool, was suggested in one study.64
Magnetic resonance imaging studies have been inconsistent, with some of them suggesting larger ventricular volumes.77–84 Functional magnetic resonance was more promising, as it showed quantitative and qualitative differences in activation of the working memory network,85 attenuation of the responsiveness to stimuli not directly related to the fatigue-inducing tasks,86 utilization of more extensive regions of the network associated with the verbal working memory system,87 impaired functioning and reduced gray-matter volume in the bilateral prefrontal cortex,88 and inactive ventral anterior cingulate after making an error.89
Single-photon emission computed tomography (SPECT) and brain electrical activity mapping scans were promising in one study,90 and SPECT scans showed more abnormalities than did magnetic resonance scans in one study (p < .025).91 Siessmeier et al.92 detected abnormalities in 18-fluorodeoxyglucose positron emission tomography in approximately half the CFS patients examined, but found that no specific pattern for CFS could be identified. Positron emission tomography showed an alteration of the serotonergic system in the rostral anterior cingulate in one study, which was suggested as an etiology.93 Recently, Puri94 described the application of proton neurospectroscopy and 31-phosphorus neurospectroscopy in chronic fatigue syndrome. It is essential to mention that evidence to date does not support routine use of the imaging modalities discussed above in evaluating potential CFS patients.
Finally, it is important to remember that a good history is more important than any available test to diagnose CFS and differentiate it from depression. The algorithm shown in Figure 1, which is based on the CDC recommendations and the results of the studies reviewed, is suggested for evaluating chronic fatigue.
Algorithm for Evaluating Chronic Fatigue Syndrome (CFS)
Before his 33-year-old son became bedridden with chronic fatigue syndrome, biochemist Ronald Davis created technologies to analyse genes and proteins faster, better and more cheaply. Now he aims his inventions at a different target: the elusive inner workings of his son’s malady.
In his office at the Stanford Genome Technology Center in Palo Alto, California, Davis holds a nanofabricated cube the size of a gaming die. It contains 2,500 electrodes that measure electrical resistance to evaluate the properties of human cells. When Davis exposed immune cells from six people with chronic fatigue syndrome to a stressor — a splash of common salt — the cube revealed that they couldn’t recover as well as cells from healthy people could. Now his team is fabricating 100 more devices to repeat the experiment, and testing a cheaper alternative — a paper-thin nanoparticle circuit that costs less than a penny to make on an inkjet printer.
Davis’s findings, although preliminary, are helping to propel research on chronic fatigue syndrome, also called myalgic encephalomyelitis (ME/CFS), into the scientific mainstream. Physicians used to dismiss the disease as psychosomatic, but studies now suggest that it involves problems in the chemical reactions, or pathways, within cells. “We now have a great deal of evidence to support that this is not only real, but a complex set of disorders,” says Ian Lipkin, an epidemiologist at Columbia University in New York City. “We are gathering clues that will lead to controlled clinical trials.”
A report released in February 2015 by the US Institute of Medicine (IOM) has helped to drive the shift. After reviewing more than 9,000 studies, an expert panel concluded that chronic fatigue syndrome was an under-studied physiological illness. “They essentially said, ‘Shame on you for not investigating this,’” says Zaher Nahle, vice-president of scientific programmes at the Solve ME/CFS Initiative, a non-profit group in Los Angeles, California.
The US National Institutes of Health (NIH) responded by doubling its planned spending on research into the condition, from around US$6 million in 2016 to $12 million in 2017. This month, Avindra Nath, a neurologist at the NIH’s National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, enrolled the first patients in a study to compare blood, spinal fluid, saliva and faecal samples from people with chronic fatigue to those without it. The scientists will analyse gut bacteria and proteins involved in metabolism and immune responses, among other things. “I call this a hypothesis-generating study,” Nath says. “Researchers are thinking deeply about how to build the field.”
From tests to treatments
Elucidating the mechanisms behind the syndrome could lead to new treatments — and the first diagnostic tests. The US Centers for Disease Control and Prevention estimate that 1 million people in the United States have the illness, but the IOM report concluded that the number could be as high as 2.5 million. Physicians use a broad list of criteria to diagnose patients, including whether a person has experienced cognitive impairment and more than six months of profound fatigue — and whether other conditions have been ruled out.
“My son can’t read. He can’t listen to music. He can’t talk. He can’t write,” Davis says. “But when the doctor does a battery of tests on him, they all come out normal.” Having a test that could signal if something was wrong in such cases would be a big help, he adds.
Lipkin has identified a distinct set of intestinal bacteria in 21 people with chronic fatigue syndrome who also had irritable bowel syndrome — conditions that often occur together. His study, accepted for publication in the journal Microbiome,also links both diseases to changes in body processes influenced by gut microbes, such as the production of vitamin B6 (D. Nagy-Szakal et al. Microbiome; in the press). And a study by another team, published in December 2016, finds problems with the function of an enzyme that is crucial for the process by which cells create energy (Ø. Fluge et al. JCI Insight 1, e89376; 2016).
Rather than seeing the thicket of metabolic, microbial and immunological data as adding to the confusion surrounding chronic fatigue, researchers are studying how the body’s systems affect each other. The current consensus is that a variety of initial triggers might converge to alter similar metabolic pathways, which ultimately leads to life-changing fatigue.
Davis says that such metabolic disruptions could impair cells’ ability to generate energy in response to stress, explaining the findings from his nanofabricated cube. First, however, he wants to ensure that his results are consistent, by comparing more data from people with chronic fatigue and those with and without other diseases.
“This is not an academic exercise,” he says. “My son is in bad, bad shape.”
Preston Gannaway for Nature
Ronald Davis holds the printed circuit he and his team developed to test for chronic fatigue syndrome.
Preston Gannaway for Nature
For Ronald Davis, research into chronic fatigue has personal significance.
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