Christina Sarris
2012 Medical Student
Scholarship Winner
Enumerate the various possible causes of Chronic Fatigue Syndrome (also referred to as
Myalgic Encephalomyelitis). Discuss the evidence for and against these causes.
Introduction
Feelings of fatigue are common complaints in the general population, yet in the majority of
cases, the fatigue is self-limited or has a known cause. Chronic Fatigue Syndrome, also referred
to as Myalgic Encephalomyelitis, is a frustrating medical condition characterized by unexplained
persistent fatigue that results in significant deficits in one’s daily social, educational, and
occupational activities. When those affected first become symptomatic, the main complaint is
generally an abrupt onset of impairing fatigue that hinders daily activity.1 Symptoms include sore
throat, muscle and joint pain, headaches, and sleep that fails to cause one to feel refreshed.
Chronic fatigue syndrome is only diagnosed when other medical conditions that may explain the
presence of the fatigue are ruled out.1
Frustratingly, the cause of Chronic Fatigue Syndrome is still poorly understood and widely
speculated. It has proven to be very difficult to identify a single cause, and much of the current
scientific thought suggests that Chronic Fatigue Syndrome is multifactorial, with both
environmental and genetic components playing a role in manifestation of the disease symptoms.2
One of the major obstacles in elucidating the causes of Chronic Fatigue Syndrome is the
difficulty of finding a large, homogeneous group of patients who fit the current definition of the
disease. One can imagine that for a patient suffering from such debilitating symptoms, with a
poorly understood cause, it can be a very trying and difficult experience. In the world of twentyfirst century medicine and science, it is often expected that we have the answers to why someone
would suffer with a disease such as this. When a patient is told that the answer is unknown, it can
be extremely disheartening and frustrating. Thus, it is critical that medical providers, as well as
the general population, become aware of the challenges associated with Chronic Fatigue
Syndrome so that compassionate care can be provided with a firm knowledge of the reality those
afflicted endure on a daily basis. As more become aware of what Chronic Fatigue Syndrome
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entails, as well as informed of the promising research currently being conducted, the future of
those suffering with the disease can be improved substantially. It is only with increased
dissemination of the current knowledge regarding Chronic Fatigue Syndrome that we can hope
to make progress towards greater understanding and potential treatments. In this review, the
current ideas surrounding the etiology and pathogenesis of Chronic Fatigue Syndrome are
discussed.
Infectious Agents and Chronic Fatigue Syndrome
Speculation over the true cause of the disease has existed since the early 1980s. In many cases of
chronic fatigue, patients have become symptomatic after combating a specific infectious disease.
Thus, infectious agents have been suggested in many instances, yet there remains no single
pathogen that can be identified in a significant proportion of cases. In 1985, two large studies of
patients with significant chronic fatigue and other symptoms were reported to have elevated
antibody titers against Epstein-Barr virus (EBV) in comparison to healthy controls3,4, and thus it
was suggested that chronic fatigue syndrome was actually caused by chronic mononucleosis
infection. This idea failed to persist as further studies did not confirm the role of EBV in cases of
chronic fatigue syndrome.5-7
Over the years, Chronic Fatigue Syndrome has been linked to a wide variety of other diseasecausing agents such as enteroviruses, cytomegalovirus, Candida albicans, Borrelia burgdorferi,
and human herpesvirus.2 Evidence implicating these agents in the disease etiology has not been
substantiated in subsequent studies. In a study of 22 monozygotic twin pairs, there was no
difference in plasma levels of antibodies to human herpesvirus (HHV)-6, HHV-8,
cytomegalovirus, and EBV between the group of twins with Chronic Fatigue Syndrome and the
healthy twins.8 Enterovirus VP1, RNA and non-cytopathic viruses have been found in stomach
biopsy specimens of Chronic Fatigue Syndrome patients, suggesting that a significant subset of
patients may have a chronic enteroviral infection.9 Giardia enteritis appears to have caused an
outbreak of Chronic Fatigue Syndrome in 5% of those infected in a large community.10 It has
also been estimated that postinfectious fatigue occurs at a rate of 12% following infection with
EBV, Q fever, or Ross River virus11, and that postinfectious fatigue has symptoms that are
clinically indistinguishable from idiopathic cases of fatigue.12 Because of such common
manifestations of fatigue symptoms following numerous infectious diseases, it has been
suggested that Chronic Fatigue Syndrome is a product of a variety of types of infections rather
than a disease with a single specific etiology.
Recently in the research of infectious agents as cause of Chronic Fatigue Syndrome were the
2009 studies suggesting that most cases were associated with a newly described gamma
retrovirus, xenotropic murine leukemia virus-related virus (XMRV).13 A study detected the virus
in 67% of patients suffering, compared with only 3.7% in healthy controls. There was much
excitement surrounding this supposed breakthrough in the frustrating disease, but soon after
publication concerns arose. Further studies could not find any evidence of XMRV infection in
the same samples tested in the 2009 study, and it was suggested that the XMRV virus arose as
the consequence of recombination between two mouse proviruses years following the first
documented description of Chronic Fatigue Syndrome. 14,15 As much excitement surrounded
XMRV and its role in the disease etiology, the heated debate stressed the importance of full
scientific validation in the search for understanding of Chronic Fatigue Syndrome.16
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Genetics and Chronic Fatigue Syndrome
Possible genetic predisposition to Chronic Fatigue Syndrome has been investigated. Using the
CDC guidelines for diagnosis of Chronic Fatigue Syndrome, a study demonstrated a
concordance of 38% in monozygotic twins versus 11% in dizygotic twins.17 Several genes have
been implicated in those affected with Chronic Fatigue Syndrome in recent studies. 18,19 NMR
metabolic profiling of a group of patients with Chronic Fatigue Syndrome has demonstrated a
significant reduction of glutamine and ornithine in the blood of those affected, suggesting a
possible disturbance in amino acid and nitrogen metabolism in disease etiology.20 Cifuentes and
Barreto identified a reliable profile of single nucleotide polymorphisms associated with Chronic
Fatigue Syndrome, suggesting markers for genetic predisposition to the disease.21 Such findings
suggest a genetic component to Chronic Fatigue Syndrome, further highlighting the disease as a
multifactorial syndrome. Large-scale genomic studies will prove invaluable to further research in
the genetics of Chronic Fatigue Syndrome in the near future.
Immunology, Neurophysiology, and Chronic Fatigue Syndrome
The associations that have been made between Chronic Fatigue Syndrome and infectious agents
have caused attention to shift towards an immunological basis for the condition. Decreased
cytotoxic activity has been shown in patients in many studies.22-24 It has been demonstrated that
those with Chronic Fatigue Syndrome may have deficient natural killer cell activation and
effector capacity.25-27 This suggests an underlying immunodeficiency in those affected that
would thus cause a more severe inflammatory response to infectious agents. Such an
inflammatory response may result in presentation with Chronic Fatigue Syndrome. Furthermore,
Zhang et al. demonstrated that the expression of TGF-B1 in peripheral blood mononuclear cells
is significantly elevated in patients with Chronic Fatigue Syndrome.28
Notably, several immune-related microRNAs have been implicated as potential biomarkers for
Chronic Fatigue Syndrome, as they play a role in regulating natural killer cells and CD8+T cell
related lytic proteins, receptors, and cytotoxic activity.29 Changes in the microRNAs of these
cells may disrupt proper functioning in immune response, thus leading to disease symptoms.
Because Chronic Fatigue Syndrome generally involves neuropsychological symptoms and
alterations in hormone levels regulated by the hypothalamus, many feel that the central nervous
system is the main site involved in the pathophysiology of the disease. Regions of decreased
cerebral blood flow were observed in patients with Chronic Fatigue Syndrome30, however these
findings were not confirmed in subsequent studies.31 Dysfunction of the hypothalamic-pituitaryadrenal axis has also been implicated, with reported studies of exaggerated adrenal
responsiveness to corticotropin infusions and lower urinary free cortisol levels in those
affected.32
It is evident that both immunologic and neurologic factors may be involved in the pathogenesis
of Chronic Fatigue Syndrome. Some argue that Chronic Fatigue Syndrome etiology lies in the
immunophysiology of the central nervous system, resulting from inflammatory events in the
brain.33 Natelson et al. demonstrated that IL-8 and IL-10 were significantly elevated in the
cerebrospinal fluid collected from patients with Chronic Fatigue Syndrome.34 A variety of
immunological and neurological abnormalities have been reported in patients with Chronic
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Fatigue Syndrome, including mitochondrial dysfunctions, abnormalities in proinflammatory
cytokines, brain pathology, and autonomic disturbances. Morris and Maes35 propose that initial
infection and immune activation caused by a variety of infectious agents leads to a state of
chronic peripheral immune activation guided by activated oxidative and nitrosative stress
pathways. Such a response produces mitochondrial damage, and subsequent ATP deficits
together with inflammation are suggested to cause the symptoms of Chronic Fatigue
Syndrome.35 A variety of neuroimmune models for the disease have been proposed very
recently, and such studies are encouraging as the etiology of this complex disease becomes
elucidated.
Conclusion
While this review does not provide a single, concrete cause for the pathogenesis of Chronic
Fatigue Syndrome, it is evident that a tremendous amount of new and promising research is
currently taking place in the field. The cause(s) of the disease are most likely multiple and
complex, involving delicate interactions among a variety of systems within the body and the
environment. With such enthusiasm for understanding the etiology of this debilitating disease, it
is unquestionable that further investigations will lead us closer to firm knowledge of the
pathogenesis and treatment options for those affected by Chronic Fatigue Syndrome. In the
meantime, it remains paramount that physicians, as well as the general public, be made aware of
the signs, symptoms, and implications of Chronic Fatigue Syndrome in order to best aid those
affected in a compassionate and knowledgeable manner.
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