Chronic Fatigue
Syndrome
What is CFS?
Chronic fatigue syndrome, or CFS, is a
debilitating and complex disorder characterized by profound fatigue
that is not improved by bed rest and that may be worsened by
physical or mental activity. Persons with CFS must often function at
a substantially lower level of activity than they were capable of
before the onset of illness. In addition to these key defining
characteristics, patients report various nonspecific symptoms,
including weakness, muscle pain, impaired memory and/or mental
concentration, insomnia, and post-exertional fatigue lasting more
than 24 hours. In some cases, CFS can persist for years. The cause
or causes of CFS have not been identified and no specific diagnostic
tests are available. Moreover, since many illnesses have
incapacitating fatigue as a symptom, care must be taken to exclude
other known and often treatable conditions before a diagnosis of CFS
is made.
Definition of CFS
A great deal of debate has surrounded the issue of
how best to define CFS. In an effort to resolve these issues, an
international panel of CFS research experts convened in 1994 to
draft a definition of CFS that would be useful both to researchers
studying the illness and to clinicians diagnosing it. In essence, in
order to receive a diagnosis of chronic fatigue syndrome, a patient
must satisfy two criteria:
• Have severe chronic fatigue of six
months or longer duration with other known medical conditions
excluded by clinical diagnosis; and
• Concurrently have four or
more of the following symptoms: substantial impairment in short-term
memory or concentration; sore throat; tender lymph nodes; muscle
pain; multi-joint pain without swelling or redness; headaches of a
new type, pattern or severity; unrefreshing sleep; and
post-exertional malaise lasting more than 24 hours. The symptoms
must have persisted or recurred during six or more consecutive
months of illness and must not have predated the fatigue.
Similar medical
conditions
A number of illnesses
have been described that have a similar spectrum of symptoms to CFS.
These include fibromyalgia syndrome, myalgic encephalomyelitis,
neurasthenia, multiple chemical sensitivities, and chronic
mononucleosis. Although these illnesses may present with a primary
symptom other than fatigue, chronic fatigue is commonly associated
with all of them.
Other conditions that may cause similar
symptoms
In addition, there are a
large number of clinically defined, frequently treatable illnesses
that can result in fatigue. Diagnosis of any of these conditions
would exclude a definition of CFS unless the condition has been
treated sufficiently and no longer explains the fatigue and other
symptoms. These include hypothyroidism, sleep apnea and narcolepsy,
major depressive disorders, chronic mononucleosis, bipolar affective
disorders, schizophrenia, eating disorders, cancer, autoimmune
disease, hormonal disorders*, subacute infections, obesity, alcohol
or substance abuse, and reactions to prescribed medications.
Other commonly observed symptoms in
CFS
In addition to the eight
primary defining symptoms of CFS, a number of other symptoms have
been reported by some CFS patients. The frequencies of occurrence of
these symptoms vary from 20 to 50% among CFS patients. They include
abdominal pain, alcohol intolerance, bloating, chest pain, chronic
cough, diarrhea, dizziness, dry eyes or mouth, earaches, irregular
heartbeat, jaw pain, morning stiffness, nausea, night sweats,
psychological problems (depression, irritability, anxiety, panic
attacks), shortness of breath, skin sensations, tingling sensations,
and weight loss.
* Not all hormonal aberrations
necessarily exclude a diagnosis of CFS.
Demographics
Several studies have helped to establish the
distribution and frequency of occurrence of CFS. While no single
study can be considered definitive — each approach has inherent
strengths and weaknesses — epidemiologic studies have greatly
improved our understanding of how common the disease is, which
individuals are the most susceptible to developing it, whether it
can be transmitted to others, and how the illness typically
progresses in individuals.
How common is CFS?
One of the earliest attempts to estimate the
prevalence of CFS was conducted by the Centers for Disease Control
and Prevention (CDC) from 1989 to 1993. Physicians in four U.S.
cities were asked to refer possible CFS patients for clinical
evaluation by medical personnel participating in the study. The
study estimated that between 4.0 and 8.7 per 100,000 persons 18
years of age or older have CFS and are under medical care. However,
these projections were underestimates and could not be generalized
to the U.S. population since the study did not randomly select its
sites. A more recent study of the Seattle area has estimated that
CFS affects between 75 and 265 people per 100,000 population. This
estimate is similar to the prevalence observed in another CDC study
conducted in San Francisco, which put the occurrence of CFS-like
disease (not clinically diagnosed) at approximately 200 per 100,000
persons. In general, it is estimated that perhaps as many as half a
million persons in the United States have a CFS-like
condition.
Who gets CFS?
This question is complex and does not have a
definitive answer. The CDC four-city surveillance study of CFS
identified a population of patients that was 98% Caucasian and 85%
female, with an average age at onset of 30 years. More than 80% had
advanced education and one-third were from upper income families.
However, these data included only patients who were under a
physician's care. There is now evidence that CFS affects all racial
and ethnic groups and both sexes. The Seattle study found that 59%
of the CFS patients were women. Eighty-three percent were Caucasian,
an underrepresentation, since over 90% of the patients in the study
were white. CDC's San Francisco study found that CFS-like disease
was most prevalent among women, among persons with household annual
incomes of under $40,000, and among blacks, and was least common
among Asians and whites. Adolescents can have CFS, but few studies
of adolescents have been published. A recently published CDC study
documented that adolescents 12 to 18 years of age had CFS
significantly less frequently than adults and did not identify CFS
in children under 12 years of age. CFS-like illness has been
reported in children under 12 by some investigators, although the
symptom pattern varies somewhat from that seen in adults and
adolescents. The illness in adolescents has many of the same
characteristics as it has in adults. However, it is particularly
important that the unique problems of chronically ill adolescents
(e.g., family social and health interactions, education, social
interactions with peers) be considered as a part of their care.
Appropriate dissemination of CFS information to patients, their
families, and school authorities is also important. CDC and the
National Institutes of Health (NIH) are currently pursuing studies
of CFS in children and adolescents.
Is CFS contagious?
There is no evidence to support the view that CFS
is a contagious disease. Contagious diseases typically occur in
well-defined clusters, otherwise known as outbreaks or epidemics.
While some earlier studies, such as investigations of fatiguing
illness in Incline Village, Nev., and Punta Gorda, Fla., have been
cited as evidence for CFS acting as a contagious illness, they did
not rigorously document the occurrence of person-to-person
transmission. In addition, none of these studies included patients
with clinically evaluated fatigue that fit the CFS case definition;
therefore, these clusters of cases cannot be construed as outbreaks
of CFS. CDC worked with state health departments to investigate a
number of reported outbreaks of fatiguing illness and has yet to
confirm a cluster of CFS cases. Implicit in any contagious illness
is an infectious cause for the disease.
Carefully designed case-control studies involving rigorously classified CFS patients and controls have found no association between CFS and a large number of human disease agents (see Possible Causes of CFS). Finally, none of the behavioral characteristics typically associated with contagious disease, such as intravenous drug use, exposure to animals, occupational or travel history, or sexual behavior, have been associated with CFS in case-control studies. It therefore seems unlikely that CFS is a transmissible disease. Nevertheless, the lack of evidence for clustering of CFS, the absence of associations between specific behavioral characteristics and CFS, and the failure to detect evidence of infection more commonly in CFS patients than in controls do not rule out the possibility that infectious agents are involved in or reflect the development of this illness. For example, important questions remain to be answered concerning possible reactivation of latent viruses (such as human herpesviruses) and a possible role for infectious agents in some cases of CFS.
Clinical course of CFS
It is vital to understand the clinical course of
CFS. This knowledge is required to facilitate communication between
physicians and patients, to evaluate possible new treatments, and to
address insurance and disability issues. The clinical course of CFS
varies considerably among persons who have the disorder; the actual
percentage of patients who recover is unknown, and even the
definition of what should be considered recovery is subject to
debate. Some patients recover to the point that they can resume work
and other activities, but continue to experience various or periodic
CFS symptoms. Some patients recover completely with time, and some
grow progressively worse. CFS often follows a cyclical course,
alternating between periods of illness and relative well being. CDC
continues to monitor the patients enrolled in the four-city
surveillance study; recovery is defined by the patient and may not
reflect complete symptom-free recovery. Approximately 50% of
patients reported "recovery," and most recovered within the first 5
years after onset of illness. No characteristics were identified
that made one patient more likely to recover than another. At
illness onset, the most commonly reported CFS symptoms were sore
throat, fever, muscle pain, and muscle weakness. As the illness
progressed, muscle pain and forgetfulness increased and the
reporting of depression decreased.
Possible causes of CFS
The cause or causes of CFS remain unknown, despite
a vigorous search. While a single cause for CFS may yet be
identified, another possibility is that CFS represents a common
endpoint of disease resulting from multiple precipitating causes. As
such, it should not be assumed that any of the possible causes
listed below has been formally excluded, or that these largely
unrelated possible causes are mutually exclusive. Conditions that
have been proposed to trigger the development of CFS include virus
infection or other transient traumatic conditions, stress, and
toxins.
A. Infectious agents
Due in part to
its similarity to chronic mononucleosis, CFS was initially thought
to be caused by a virus infection, most probably Epstein-Barr virus
(EBV). It now seems clear that CFS cannot be caused exclusively by
EBV or by any single recognized infectious disease agent. No firm
association between infection with any known human pathogen and CFS
has been established. CDC's four-city surveillance study found no
association between CFS and infection by a wide variety of human
pathogens, including EBV, human retroviruses, human herpesvirus 6,
enteroviruses, rubella, Candida albicans, and more recently
bornaviruses and Mycoplasma. Taken together, these studies suggest
that among identified human pathogens, there appears to be no causal
relationship for CFS. However, the possibility remains that CFS may
have multiple causes leading to a common endpoint, in which case
some viruses or other infectious agents might have a contributory
role for a subset of CFS cases.
B. Immunology
It has been proposed
that CFS may be caused by an immunologic dysfunction, for example
inappropriate production of cytokines, such as interleukin-1, or
altered capacity of certain immune functions. One thing is certain
at this juncture: there are no immune disorders in CFS patients on
the scale traditionally associated with disease. Some investigators
have observed anti-self antibodies and immune complexes in many CFS
patients, both of which are hallmarks of autoimmune disease.
However, no associated tissue damage typical of autoimmune disease
has been described in patients with CFS. The opportunistic
infections or increased risk for cancer observed in persons with
immunodeficiency diseases or in immunosuppressed individuals is also
not observed in CFS. Several investigators have reported lower
numbers of natural killer cells or decreased natural killer cell
activity among CFS patients compared with healthy controls, but
others have found no differences between patients and controls.
T-cell activation markers have also been reported to have differential _expression in groups of CFS patients compared with controls, but again, not all investigators have consistently observed these differences. One intriguing hypothesis is that various triggering events, such as stress or a viral infection, may lead to the chronic _expression of cytokines and then to CFS. Administration of some cytokines in therapeutic doses is known to cause fatigue, but no characteristic pattern of chronic cytokine secretion has ever been identified in CFS patients. In addition, some investigators have noted clinical improvement in patients with continued high levels of circulating cytokines; if a causal relationship exists between cytokines and CFS, it is likely to be complex. Finally, several studies have shown that CFS patients are more likely to have a history of allergies than are healthy controls. Allergy could be one predisposing factor for CFS, but it cannot be the only one, since not all CFS patients have it.
C. Hypothalamic-pituitary adrenal (HPA)
axis
Multiple laboratory studies have suggested that the
central nervous system may have an important role in CFS. Physical
or emotional stress, which is commonly reported as a pre-onset
condition in CFS patients, activates the
hypothalamic-pituitary-adrenal axis, or HPA axis, leading to
increased release of cortisol and other hormones. Cortisol and
corticotrophin-releasing hormone (CRH), which are also produced
during the activation of the HPA axis, influence the immune system
and many other body systems. They may also affect several aspects of
behavior. Recent studies revealed that CFS patients often produce
lower levels of cortisol than do healthy controls. Similar hormonal
abnormalities have been observed by others in CFS patients and in
persons with related disorders like fibromyalgia. Cortisol
suppresses inflammation and cellular immune activation, and reduced
levels might relax constraints on inflammatory processes and immune
cell activation. As with the immunologic data, the altered cortisol
levels noted in CFS cases fall within the accepted range of normal,
and only the average between cases and controls allows the
distinction to be made. Therefore, cortisol levels cannot be used as
a diagnostic marker for an individual with CFS. A placebo-controlled
trial, in which 70 CFS patients were randomized to receive either
just enough hydrocortisone each day to restore their cortisol levels
to normal or placebo pills for 12 weeks, concluded that low levels
of cortisol itself are not directly responsible for symptoms of CFS,
and that hormonal replacement is not an effective treatment.
However, additional research into other aspects of neuroendocrine
correlates of CFS is necessary to fully define this important, and
largely unexplored, field.
D. Neurally mediated hypotension
Rowe
and coworkers conducted studies to determine whether disturbances in
the autonomic regulation of blood pressure and pulse (neurally
mediated hypotension, or NMH) were common in CFS patients. The
investigators were alerted to this possibility when they noticed an
overlap between their patients with CFS and those who had NMH. NMH
can be induced by using tilt table testing, which involves laying
the patient horizontally on a table and then tilting the table
upright to 70 degrees for 45 minutes while monitoring blood pressure
and heart rate. Persons with NMH will develop lowered blood pressure
under these conditions, as well as other characteristic symptoms,
such as lightheadedness, visual dimming, or a slow response to
verbal stimuli. Many CFS patients experience lightheadedness or
worsened fatigue when they stand for prolonged periods or when in
warm places, such as in a hot shower. These conditions are also
known to trigger NMH. One study observed that 96% of adults with a
clinical diagnosis of CFS developed hypotension during tilt table
testing, compared with 29% of healthy controls. Tilt table testing
also provoked characteristic CFS symptoms in the patients. A study
(not placebo-controlled) was conducted to determine whether
medications effective for the treatment of NMH would benefit CFS
patients. A subset of CFS patients reported a striking improvement
in symptoms, but not all patients improved. A placebo-controlled
trial of NMH medications for CFS patients is now in progress.
F. Nutritional deficiency
There is no published scientific evidence that CFS
is caused by a nutritional deficiency. Many patients do report
intolerances for certain substances that may be found in foods or
over-the-counter medications, such as alcohol or the artificial
sweetener aspartame. While evidence is currently lacking for
nutritional defects in CFS patients, it should also be added that a
balanced diet can be conducive to better health in general and would
be expected to have beneficial effects in any chronic illness.
Diagnosis of CFS
How physicians diagnose CFS
If a patient
has had 6 or more consecutive months of severe fatigue that is
reported to be unrelieved by sufficient bed rest and that is
accompanied by nonspecific symptoms, including flu-like symptoms,
generalized pain, and memory problems, the physician should further
investigate the possibility that the patient may have CFS. The first
step in this investigation is obtaining a detailed medical history
and performing a complete physical examination of the patient.
Initial testing should include a mental status examination, which
ordinarily will involve a short discussion in the office or a brief
oral test. A standard series of laboratory tests of the patient's
blood and urine should be performed to help the physician identify
other possible causes of illness. If test results suggest an
alternative explanation for the patient's symptoms, additional tests
may be performed to confirm that possibility. If no cause for the
symptoms is identified, the physician may render a diagnosis of CFS
if the other conditions of the case definition are met. A diagnosis
of idiopathic chronic fatigue could be made if a patient has been
fatigued for 6 months or more, but does not meet the symptom
criteria for CFS.
Appropriate tests for routine diagnosis of
CFS
While the number and type of tests performed may vary
from physician to physician, the following tests constitute a
typical standard battery to exclude other causes of fatiguing
illness: alanine aminotransferase (ALT), albumin, alkaline
phosphatase (ALP), blood urea nitrogen (BUN), calcium, complete
blood count, creatinine, electrolytes, erythrocyte sedimentation
rate (ESR), globulin, glucose, phosphorus, thyroid stimulating
hormone (TSH), total protein, transferrin saturation, and
urinalysis. Further testing may be required to confirm a diagnosis
for illness other than CFS. For example, if a patient has low levels
of serum albumin together with an above-normal result for the blood
urea nitrogen test, kidney disease would be suspected. The physician
may choose to repeat the relevant tests and possibly add new ones
aimed specifically at diagnosing kidney disease. If autoimmune
disease is suspected on the basis of initial testing and physical
examination, the physician may request additional tests, such as for
antinuclear antibodies.
Psychological/neuropsychological
testing
In some individuals it may be beneficial to assess
the impact of fatiguing illness on certain cognitive or reasoning
skills, e.g., concentration, memory, and organization. This may be
particularly relevant in children and adolescents, where academic
attendance, performance, and specific educational needs should be
addressed. Personality assessment may assist in determining coping
abilities and whether there is a co-existing affective disorder
requiring treatment.
Theoretical and experimental
tests
A number of tests, some of which are offered
commercially, have no demonstrated value for the diagnosis of CFS.
These tests should not be performed unless required for diagnosis of
a suspected exclusionary condition (e.g., MRI to rule out suspected
multiple sclerosis) or unless they are part of a scientific study.
In the latter case, written informed consent of the patient is
required. No diagnostic tests for infectious agents, such as
Epstein-Barr virus, enteroviruses, retroviruses, human herpesvirus
6, Candida albicans, and Mycoplasma incognita, are diagnostic for
CFS and as such should not be used (except to identify an illness
that would exclude a CFS diagnosis, such as mononucleosis). In
addition, no immunologic tests, including cell profiling tests such
as measurements of natural killer cell (NK) number or function,
cytokine tests (e.g., interleukin-1, interleukin-6, or interferon),
or cell marker tests (e.g., CD25 or CD16), have ever been shown to
have value for diagnosing CFS. Other tests that must be regarded as
experimental for making the diagnosis of CFS include the tilt table
test for NMH, and imaging techniques such as MRI, PET-scan, or
SPECT-scan. Reports of a pathway marker for CFS as well as a urine
marker for CFS are undergoing further study; however, neither is
considered useful for diagnosis at this time.
Careful consideration
of information about CFS
Because
the cause of CFS has not been identified and its effect on the body
is not well understood, periodically new unvalidated beliefs about
cures and causes of CFS are widely circulated. These may be based on
one or more recent reports from the peer-reviewed scientific
literature, or they may evolve from the anecdotal remarks of
clinicians or scientists at medical meetings. In some cases the
origin is obscure. Even work that is of sufficiently high caliber to
be published in the scientific literature is not without limitations
and design flaws, and all published work needs to be verified and
expanded on by others before it can be applied with confidence in
clinical situations. With regard to some stories that are currently
circulating about CFS: (i) there is no evidence that CFS patients
lose their fingerprints; (ii) there is no scientific evidence of any
nutritional deficiency in CFS patients; and (iii) suicides of CFS
patients have been reported, but the rate of occurrence has not been
well-studied and it is not known whether the rate is higher or lower
than what would be expected in the general population. It is not
practical to address all of the information that circulates or
emerges regarding CFS. Simply be advised to be wary of information
that points to sure cures or that alludes to pathological damage as
a consequence of CFS. Specific questions should be discussed with
the patient's physician, local or state health department, CDC, or
one of the national patient support organizations.
Support
groups
Chronic Fatigue Syndrome (CFS) patients may find it
therapeutic to meet with other people who have this illness, and
often this can be accomplished by joining a local CFS support group.
Review the following information carefully to locate a resource that
is reliable, convenient, and comfortable to you.
CFS Patient Support Groups in the United States
CFS Patient Support Groups outside the United States
This information was developed by the Centers for Disease Control and Prevention, National Center for Infectious Diseases.
Centers for Disease Control and Prevention, National Center for Infectious Diseases, Division of Viral and Rickettsial Diseases. CFS Information. Available at: http://www.cdc.gov/ncidod/diseases/cfs/about/index.htm. Last accessed May 24, 2004.
The information in this document is for
general educational purposes only. It is not intended to substitute
for personalized professional advice. Although the information was
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consequences resulting from its use. For further information,
consult a physician and the organization referred to
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