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Chronic Fatigue Syndrome
Chronic fatigue syndrome (CFS) is an illness characterized by prolonged, debilitating fatigue and multiple
nonspecific symptoms such as headaches, recurrent sore throats, muscle and joint pains, and cognitive
complaints. Profound fatigue, the hallmark of the disorder, can come on suddenly or gradually and persists
or recurs throughout the period of illness. Unlike the short-term disability of an acute infection, CFS
symptoms by definition linger for at least 6 months and often for years.
An estimated one-quarter of all patients seeing general practitioners complain of prolonged fatigue, a
symptom common to many illnesses. Several studies indicate that only a small fraction of these patients meet
the criteria for chronic fatigue syndrome.
Despite multidisciplinary investigations into the cause of CFS, its etiology remains unknown. Similarly, no
specific diagnostic tests or therapies for CFS exist. A supportive program of patient management--including
symptom-based treatment, education about the disease, and regular follow-up visits to rule out alternative
diagnoses--can offer reassurance, dispel unfounded beliefs about CFS or its treatment, and help patients
and their families adjust to living with this chronic illness.
CFS does not appear to be a new illness. Relatively small outbreaks of similar disorders have been
described in the medical literature since the 1930s. Furthermore, case reports of comparable illnesses date
back several centuries, some possibly linked to bacterial, viral, or protozoal infections such as brucellosis,
yellow fever, hepatitis, influenza, and malaria.
Fatigue syndromes also have been long recognized outside the setting of an infectious illness. For example,
the clinical descriptions of CFS and the rheumatologic disorder fibromyalgia, first described in the l9th
century, overlap considerably. CFS and depression also share some symptoms.
Interest in what now is called CFS was renewed in the mid-1980s after several studies found slightly higher
levels of antibody to Epstein-Barr virus (EBV) in patients with CFS-like symptoms than in healthy
individuals. Most of these patients had experienced an episode of infectious mononucleosis a few years
before the onset of their new chronic, debilitating illness. As a result, for a time the CFS-like illness became
popularly termed "chronic EBV."
In subsequent investigations, it became clear that elevated EBV antibody titers were not diagnostic for CFS:
Some healthy people have high EBV titers and some people with CFS do not. Currently, it is not
considered useful to test for antibodies to EBV in a patient with symptoms suggestive of CFS. More than
90 percent of adults in developed countries have been exposed to EBV by age 30, and moderately elevated
antibody titers have not been associated with any EBV-related disease. Chronic EBV is an inappropriate
label for this illness and should be abandoned.
The name "chronic fatigue syndrome," chosen because it reflects the most common symptom, was selected
for the illness by a group of experts in 1988. When the International CFS Study Group updated the case
definition, they decided to retain this name until the discovery of a specific cause of or marker for the illness
suggests a more fitting name.
Symptom complexes similar to CFS also are known as epidemic neuromyasthenia, myalgic
encephalomyelitis, postviral fatigue syndrome, and chronic fatigue and immune dysfunction syndrome in
different parts of the world. No immune dysfunction specific to CFS has been found, however, and there is
no evidence linking encephalomyelitis to the pathology of the illness.
Most CFS cases are sporadic. No published data indicate that CFS is contagious, that it can be transmitted
through intimate or casual contact or by blood transfusion, or that people with CFS need to be isolated in
Occasionally, close contacts, including family members, become ill with CFS at about the same time. Also,
clusters of CFS-like illnesses have been reported during the past 60 years in various families, communities,
or workplaces. Outbreaks of CFS are unusual, however, and have proven difficult to validate. Case clusters
should be reported to state health officials for investigation.
Although the typical patient seeking medical care for CFS is a Caucasian woman between her mid-twenties
and late forties, patients of both sexes across a wide range of ages, races, and socioeconomic groups have
been affected. The demographics of the population currently diagnosed with CFS may be biased by cultural
differences and access to medical care, an issue addressed in the design of more recent epidemiologic
Without objective diagnostic criteria, the prevalence of CFS is difficult to measure. The Centers for Disease
Control and Prevention (CDC) estimates the minimum CFS prevalence rate in the United States is 4 to 10
cases per 100,000 adults 18 years of age or older (based on physician-referred patients from four cities
evaluated by the 1988 case definition and adjusted for age, sex, and race). A several-fold higher prevalence
rate of self-reported CFS-like illness exists according to preliminary, unpublished results from a
17,000-person survey coordinated by CDC in an unreferred San Francisco population, and to independent
findings of smaller community-based surveys. However, in the CDC survey most CFS-like illness appeared
to be due to other causes. When these people were evaluated by a physician, the rate of illness consistent
with the 1988 CFS case definition was approximately twice that identified by the physician-referred study.
This experience underscores the importance of physician evaluation to rule out other, potentially treatable
The usefulness of the case definition in pediatric populations in the United States is currently being evaluated.
Recent CDC studies indicate that the prevalence rate in adolescents is slightly lower than that in adults.
Cases in children under 12 years old appear to be much less common.
Outside the United States, CFS and CFS-like syndromes have been reported widely, including in Europe,
Australia, New Zealand, Canada, Iceland, Japan, Russia, and South Africa.
CFS often begins abruptly, but sometimes the onset is gradual. In about one-third of cases, the sudden
onset follows a respiratory, gastrointestinal, or other acute infection with flu-like symptoms, including
mononucleosis. Other cases develop after emotional or physical traumas such as bereavement or surgery.
Besides a debilitating fatigue unrestored by rest, common symptoms of CFS include more intense or
changed patterns of headaches; reduced short-term memory or concentration; recurrent sore throats; tender
lymph nodes; muscle discomfort or pain; joint pain without joint swelling or redness; unrefreshing sleep; and
postexertional malaise lasting more than 24 hours. The severity of CFS symptoms varies broadly among individuals.
A majority of CFS patients also report mild to moderate symptoms of anxiety or depression. Several
studies report a high rate of coexisting psychiatric diagnoses in CFS patients, greater than that found in
patients with other debilitating medical illnesses such as rheumatoid arthritis, multiple sclerosis, and
neuromuscular disease. It is important to note, however, that about 20 to 40 percent of carefully evaluated
CFS patients do not have depression or another psychiatric illness.
Some studies have found a significantly greater prevalence of allergy in CFS patients than in the general
population. Many CFS patients have a history of allergies years before the onset of the syndrome.
Sometimes patients report a worsening of allergic symptoms or the onset of new allergies after becoming ill with CFS. Because allergies are so common in people with CFS, it is important to differentiate those
symptoms that are allergy-related and thus amenable to specific therapies.
Although CFS can persist for many years, longitudinal and follow-up studies indicate that CFS generally is
not a progressive illness. The symptoms usually are most severe in the first year or two. Thereafter, the
symptoms typically stabilize and then persist chronically, wax and wane, or improve. Most patients partially
recover, some fully recover, and others recover and relapse. Currently, an individual's course of illness
cannot be predicted. No long-term health risks, such as an increased risk of cancer, have been associated
with having CFS.
Various immunologic findings have been described in patients with CFS, but no single immunologic
disturbance has been reported consistently or yet been identified as typical of the syndrome, nor have these
findings correlated with symptoms or prognosis. The disturbances include depressed natural killer (NK) cell
activity, modest increases in the number of circulating lymphocytes that appear to be activated, and slightly
elevated levels of circulating immune complexes. All of these findings point to general differences between
patient populations and control groups, but none is specific for CFS or abnormal in all CFS patients. In
addition, immunologic changes like these often accompany various infections as well as physically or
emotionally stressful experiences. The character, epidemiology, and prognosis of CFS also are distinct from
those of major immune deficiency disorders, including acquired immunodeficiency syndrome (AIDS): For
example, there is no published evidence that CFS is associated with opportunistic infections or an increased
risk for the development of malignancies.
For many patients, the cognitive impairment they experience is one of the most debilitating and disconcerting
symptoms. CFS patients do not exhibit gross dementia, but most often report an inability to concentrate,
unusual forgetfulness, and difficulty with information processing and word finding. CFS patients often
subjectively report worse cognitive problems than are indicated by objective evidence obtained with formal
testing. Whether this discrepancy reflects some distortion in perceived symptoms on the part of the patient
or a deficiency in test methodology is unresolved at this time. Although most controlled studies have found
no significant and reproducible neuropsychologic abnormalities in CFS patients, research provides some
evidence that a subset of CFS patients have deficits in complex auditory cognitive processing.
Some CFS patients report other neurologic symptoms, including paresthesias, disequilibrium, and visual
blurring. These usually are not accompanied by any evidence of gross or localized neurologic signs.
Some studies using magnetic resonance imaging (MRI) or SPECT scanning have found brain abnormalities
associated with CFS while others have not. The positive reports are preliminary and unconfirmed. The
abnormalities are neither detected consistently nor are they specific to the syndrome. The use of MRI,
SPECT scans, or other neuroimaging techniques in CFS patients cannot be justified at this time unless the
differential diagnosis indicates otherwise.
Evaluation of Patients
|Table 2. Some conditions That Can Explain Chronic Fatigue
Unresolved hepatitis B or C
Alcohol or substance abuse
Latrogenic, e.g., medication side effects
System lupus eruthematosus
Major depressive disorder
The patient reporting that chronic fatigue is interfering with his or her life should
be treated with compassion and evaluated carefully. Because people with CFS
usually do not look as sick as they feel, family members, friends, employers,
and physicians may doubt the patient's claim of illness.
The diagnosis of CFS is primarily one of exclusion. Table 2 lists some
conditions that should be considered and ruled out as alternative explanations
for presenting symptoms in patients with chronic fatigue. This list may be useful
but is not exhaustive. (See appendix for further details.)
CFS symptoms overlap with those of fibromyalgia, Lyme borreliosis, mild
systemic lupus erythematosus (SLE), early or mild multiple sclerosis (MS),
depression, and numerous other well-recognized disorders.
CFS and fibromyalgia, closely related illnesses, commonly coexist in the same
patient. The diagnosis of fibromyalgia, however, unlike that of CFS, requires
the detection of discrete tender points. Also, the typical fibromyalgia patient
may be slightly older and have more widespread soft-tissue pain. A diagnosis
of fibromyalgia does not exclude one of CFS, but when analyzing data from
research studies, CFS patients with this disorder should be subgrouped.
A history of possible tick exposure, the typical Lyme rash (erythema
chronicum migrans), and antibodies to Borrelia burgdorferi suggest the
diagnosis of Lyme disease. It has recently been recognized, however, that B.
burgdorferi can trigger CFS in some people who have received adequate
treatment for Lyme disease, are refractory to further antibiotic treatment, and
have no evidence of persisting infection with the spirochete.
In other illnesses like SLE and MS, debilitating chronic fatigue can be more
prominent than rheumatologic or neurologic symptoms, but the presence of
objective physical findings, laboratory abnormalities, and illness progression
point to the correct diagnosis.
Psychiatric illnesses that most resemble CFS include major depressive
episode, panic disorder, generalized anxiety disorder, and somatization
disorder. Because subtle psychiatric problems can be difficult to recognize,
consultation with a psychiatrist or psychologist may benefit the evaluation and
management of some patients. The relationship between psychiatric illness and
CFS is complex, interactive, and not yet well understood. For this reason, a
history of prior or current depressive episodes does not exclude a diagnosis of
CFS, but the revised CFS case definition recommends stratifying these
patients when analyzing data for research purposes. For the case definition, a
history of major depression with psychotic or melancholic features, bipolar
affective disorder, schizophrenia, delusional disorder, dementia, active substance or alcohol abuse, anorexia
nervosa, or bulimia excludes a diagnosis of CFS because these illnesses preclude the reliable determination
of the core symptoms of CFS.
|Table 3. Initial Laboratory Workup
Complete blood count with differential
Thyroid function test (TSH may suffice)
Erythrocyte sedimentation rate
A reasonable initial laboratory workup is listed in table 3. Significantly
abnormal results on any of these tests should prompt consideration of other
medical diagnoses. It is also prudent to consider the possibility of infection with
the human immunodeficiency virus (HIV). Subsequent workup should be
guided by the clinical picture. The patient's medical history--particularly usage
of prescription and over-the-counter drugs, including vitamins and
supplements--a complete physical examination, and a mental status
examination to screen for any major abnormalities will help determine the need
for more laboratory tests.
Children and adolescents
The presentation of CFS in children and adolescents is similar to that in adults
but is less well studied. A supportive approach can help reduce the anxiety of
young patients and their families during the evaluation period. CFS can be
difficult to diagnose in younger children who have trouble describing illness
symptoms and articulating their concerns, leaving the parents to recount their
perceptions of their child's medical history. As for any chronic illness in a child,
it is important to direct careful attention to family functioning to identify and
address underlying family problems or psychopathology that may be
contributing to the CFS-like symptoms. Age-appropriate tests must be used,
as needed, to assess stress, depression, and anxiety.
The physician should be prudent in applying the diagnostic label CFS to a
young person. In the event that the symptoms are misdiagnosed as CFS, the
potential consequences of not providing the proper treatment or of possibly
perpetuating inappropriate illness behaviors--especially the effects on
psychosocial development and identity--may be even more profound than in
an adult. It is essential to schedule regular follow-up visits to offer reassurance,
make adjustments in treatments, and note any changes that could indicate
another source of the symptoms.
CFS is debilitating in all patients, disabling in some, but usually not progressive. The debility and disability
stem from a combination of symptoms such as fatigue, muscle and joint pain, sleep disturbances, cognitive
impairment, and, in some patients, from associated depression. Patients need both symptomatic treatment
and emotional support (see table 4).
|Table 4. Elements in CFS Patient Management
|Establish therapeutic alliance with patient
Dispel misinformation about the disease
Use a medical team approach
Prescribe symptomatic treatments
Urge stress reduction
Introduce slowly graduated exercise
Suggest rehabilitation therapy to develop energy conservation techniques
Schedule regular follow-up visits
Give emotional support
It is vitally important for the physician to be the patient's advocate. Forging a
therapeutic alliance based on trust and open exchange can counter
misinformation about the disease. In the absence of any proven treatments,
carefully selected empiric therapies should be tried. At the same time, patients
need to be cautioned to avoid using exotic, untested remedies that may be
harmful. Physicians should continually be on the lookout for other medical
problems and avoid the assumption that every new sign or symptom is a
manifestation of CFS. It is common practice to schedule follow-up visits every
6 months or whenever there is a disconcerting new finding or complaint.
It is important for people with CFS to slow the pace of their lives, and avoid
or reduce their exposure to situations that are physically or psychologically
stressful. Having a chronic illness is stressful in itself. Counseling can help both
the patient and his or her family adjust to the uncertain course of the illness and
its effects on roles and relationships in and outside the family. Some patients
benefit from participation in CFS support groups. The patient and the family
need to realize that no definitive diagnostic or therapeutic approaches exist and
no specific nutritional program has proved valuable, although a balanced diet
and rest generally enhance well-being. Referrals to professionals who can help
patients with practical matters, such as applying for disability and obtaining
home health care, if needed, can help some patients and their families better
manage this illness.
Psychiatric problems need to be actively considered and treated. Ideally, the
psychiatrist should have experience in treating patients with CFS or related
chronic illnesses and should become part of the medical care team, if possible,
to reassure the patient that he or she is not just being passed on to another
specialist. Recent data also indicate that cognitive behavioral therapy may
improve disability and symptoms in some patients whose coping behaviors or
perceptions of their illness inhibit their recovery.
Patients should receive guidance about how to balance activity and rest, to set
realistic goals, to create flexible plans to account for fluctuations in energy and
symptoms, and to remain optimistic about recovery. Referral to an occupational therapist who can design
strategies for conserving energy and, if appropriate, to a vocational rehabilitation therapist, may help CFS
patients improve their functional capacity, limit deconditioning, and enhance their lives, even if their
symptoms remain the same.
Abrupt resumption of exercise usually exacerbates symptoms and should be avoided. At a minimum,
however, patients should be encouraged to engage in any form of gradually reintroduced physical activity to
tolerance. A slowly graduated exercise program tailored to the individual--if warranted, through an ongoing program of physical therapy--can build confidence in the patient that some level of physical conditioning can be achieved.
For children and adolescents, the physician should work with the school to limit class time, if necessary, and to resume normal attendance gradually. Home tutoring may be an alternative.
Although there is no one drug or group of drugs specific for CFS, symptomatic treatment is helpful. To
reduce the muscle and joint pains, headaches, or feelings of feverishness associated with the illness, aspirin,
other nonsteroidal anti-inflammatory drugs, or acetaminophen may be prescribed. Nonsedating
antihistamines may help relieve any prominent allergic symptoms.
Double-blind, placebo-controlled CFS therapy trials have found no or limited utility for most other drugs
tested. The first such trial reported found the antiviral drug acyclovir to be no better than placebo, with a
large portion of the patients on placebo reporting improvement. Although some physicians prescribe
intramuscular or intravenous gamma globulin, three controlled clinical trials of intravenous immunoglobulin
have yielded conflicting results regarding efficacy. Despite the high prevalence of allergies in the CFS
population, a trial of terfenadine found no benefit for patients with CFS. One placebo-controlled trial of
essential fatty acids found some efficacy while another did not. Injectable liver extract also did not appear to
be effective in controlled clinical trials.
Recently, a strong link between CFS and neurally mediated hypotension was reported. The study found that
22 of 23 CFS patients tested positive for neurally mediated hypotension by specialized tilt-table testing and
pharmacologic provocation. Of those who tested positive, 16 reported full or partial recovery from fatigue
after uncontrolled treatment with fludrocortisone, beta-adrenergic blocking agents, and disopyramide, alone
or in combination. A randomized, placebo-controlled study is under way to attempt to validate these
Several additional empiric therapies have been tried for CFS. Because well-designed clinical trials have
demonstrated the benefit of low doses of tricyclic antidepressant drugs in fibromyalgia, tricyclics such as
amitriptyline, desipramine, doxepin, and nortriptyline are widely prescribed for CFS patients. Anecdotal
experience with tricyclics and selective serotonin reuptake inhibitors (SSRIs) generally has been positive.
Besides targeting depression, some antidepressants appear to act by improving the quality of sleep and/or
decreasing pain. However, CFS patients often report that antidepressants given in full, therapeutic doses
exacerbate their fatigue. It may be necessary to escalate doses very slowly and urge patience in detecting
benefit, or to try the more activating antidepressants such as desipramine, SSRIs such as fluoxetine and
sertraline, or monamine oxidase inhibitors. Many CFS patients are extremely sensitive to these drugs, and it
is common practice to start a patient at one-tenth to one-quarter of the usual clinical dose.
Although adequate controlled trials are lacking, some CFS patients who also suffer from panic disorder or
anxiety have reported benefit from anxiolytic medications such as alprazolam, clonazepam, other
benzodiazepines, or buspirone.
Because no specific regimen for treating CFS exists, several different treatment approaches may have to be
tried before the patient reports benefit. Both the physician and the patient need to be open to reasonable
treatment options and appreciate that improvement may occur in small increments.
The etiology of CFS continues to be vigorously investigated. Because of the syndrome's heterogeneity,
many researchers argue against it being a discrete disease caused by one agent. For example, although
some CFS patients exhibit any of a variety of immunologic disturbances, no single pattern of disturbances
appears consistently, and many patients test in the normal range. Sometimes the syndrome appears to follow
an infection or physical or psychological trauma, but cases also develop gradually without an obvious
triggering event. Higher-than-normal antibody levels to a variety of viruses appear in some but not all
patients. Finally, although many people with CFS suffer from anxiety or depression, which may or may not
predate their CFS, about one-third of CFS patients do not have a psychiatric illness.
Instead of a discrete disease, many researchers believe CFS represents a common set of symptoms
triggered by different combinations of various infectious and noninfectious factors. This idea is consonant
with a model proposing that, like hypertension or anemia, CFS be considered a clinical condition.
Despite extensive efforts by many laboratories, no published data implicate a specific virus or other microbe
as the cause of CFS. Several efforts to confirm initial reports that novel retroviruses or a spumavirus might
be involved in CFS also have been unsuccessful. Known or newly discovered viruses continue to be
investigated as possible factors in causing the illness or influencing its course.
It appears likely, however, that infectious agents, among other stressors, can precipitate the syndrome. The
best evidence comes from carefully studied cases of new infection with B. burgdorferi, in which CFS was
triggered following apparent resolution of the bacterial infection.
A variety of common viruses can be reactivated in some CFS patients, including the herpes viruses EBV,
cytomegalovirus, herpes simplex virus 1 and 2, and human herpes virus 6. Most investigators believe virus
reactivation could be occurring secondarily to some immunologic disturbance. No direct evidence links any
of these viruses, or enteroviruses such as coxsackievirus and echovirus, to the cause of CFS or its
Other theories of CFS etiology focus on the immune system. One theory postulates that the illness involves a
constant antigenic challenge to the immune system and, as a consequence, a constant immunologic response
to that challenge. A related idea suggests that after controlling or eliminating the antigen involved in the acute,
precipitating disease, the immune system remains in high gear instead of returning to normal. According to
these ideas, the immune system produces excess levels of inflammatory mediators and cytokines, such as
interleukins and interferons, which trigger the flu-like symptoms of CFS. However, consistent evidence of
abnormal cytokine levels in CFS patients have not been found.
Central nervous system model
The central nervous system figures prominently in other theories of CFS etiology that try to unify the
disparate biological and clinical features of the syndrome. According to one such theory, the interaction
between various events (for example, infectious agents, physical or emotional stress, environmental
exposures, genetics, and psychiatric history) prior to the onset of the syndrome ultimately converge in a
clinical condition that is perpetuated by a specific pathologic response to those events. This pathologic
response may represent a disruption of a common biologic pathway coordinated by the central nervous
Supporting this theory is the finding of a confirmed, well-controlled neuroendocrine study. CFS patients as a
group were found to have a subtle deficiency of the stress hormone cortisol, the opposite of the
hypercortisolism that characterizes melancholic depression, one of the most common subtypes of major
depression. Not only do these observations suggest that disturbances in the hypothalamic-pituitary-adrenal
(HPA) axis play a role in both syndromes, the results attest to the biologic distinctions between CFS and a
principal form of major depression while offering one possible explanation for their overlapping clinical
presentations. Because cortisol is a potent suppressor of immune responses, this finding also may explain the
immune disturbances seen in some people with CFS. Hypocortisolism also has been reported in patients
with fibromyalgia, an illness strikingly similar to CFS.
Although researchers have just begun to explore at the molecular level the interactions between stress, the
neuroendocrine system, and the immune response, this is an active area of research.
Recently reported preliminary research also suggests considerable overlap between CFS and neurally
mediated hypotension, a potentially treatable illness (see Drug Treatments). This finding is consistent with the
neuroendocrine abnormality described above and, if confirmed, would support the theory that CFS is a
multisystem illness with prominent CNS involvement.
A great deal of controversy and speculation surrounds CFS: Is it a single disorder or a heterogeneous mix
of problems? What is its relationship to infections, to the immune system, to neurally mediated hypotension,
and to mood disturbances? How can it best be treated? These and many more issues fuel the continuing
broad debate, often leaving patients and their physicians frustrated. For now, neither physicians nor
researchers have all the answers. But in treating people with CFS, physicians can draw on practices that
have always made medicine a valued art: exclude alternative problems, ameliorate symptoms, and offer
guidance with compassion.
For more information on classification and research groups, visit the NIH website.
Information provided by NIH.