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Chronic Fatigue Syndrome
A Pamphlet for Physicians
U.S. Department of Health and Human Services
Public Health Service
National Institutes of Health
NIH Publication No. 92-484
May 1992
Table of Contents
Introduction
1
Epidemiology
2
Historical Perspective
3
Clinical Picture
4
Evaluation of Patients
5
Immunologic Features
6
Neuropsychologic Features
7
Etiologic Theories
8
Patient Management
9
Conclusion
11
Appendix
12
Page 1
Chronic Fatigue Syndrome
Introduction
Chronic fatigue syndrome (CFS) is an illness characterized by debilitating
fatigue and several flu-like symptoms such as pharyngitis, adenopathy, low-
grade fever, myalgia, arthralgia, headache, difficulty concentrating, and
exercise intolerance. These nonspecific symptoms can make the syndrome
difficult to identify. Profound fatigue -- the earmark of the disorder --
usually comes on suddenly and persists or relapses throughout the course of
the illness. But unlike the short-term fatigue and malaise that often
accompanies an acute infection, by definition, CFS symptoms linger for at
least 6 months, and often for years.
Chronic fatigue is a common complaint in primary care practice. No evidence
exists to suggest that most patients with chronic fatigue have CFS. Indeed,
CFS is probably an uncommon cause of chronic fatigue.
When evaluating patients with chronic fatigue of unknown origin, physicians
can use the definition of CFS in the Appendix as a guide. This detailed
definition was developed for research use under the leadership of the Centers
for Disease Control. It was published in Annals of Internal Medicine in
March 1988. Because the disease is still poorly understood, however, the
outlined criteria should be considered provisional.
Most investigators studying CFS believe that the syndrome has many possible
causes. For example, various infectious agents often trigger the onset of
CFS. Preliminary research also shows a variety of immunologic disturbances
in some patients. No single pattern of disturbances appears consistently,
however, and in general, patients are
Page 2
not clinically immunocompromised: they do not develop opportunistic
infections. In fact, the character, epidemiology, and prognosis of CFS is
quite distinct from that of major immune deficiency disorders such as AIDS.
Several different latent viruses also appear to be reactivated in some CFS
patients, although reactivation has not been shown in all patients, and it is
not clear that any of these viruses are causally related to CFS or its
symptoms. Many patients with CFS also present with anxiety or depression.
In summary, as with most chronic illness, CFS has both physical and
psychiatric manifestations.
Epidemiology
Most cases of CFS are sporadic: the patient does not have a close contact who
has developed a similar illness. Infrequently, however, close contacts,
including family members, become ill with CFS at about the same time. During
the past 60 years, several apparent epidemics of this illness affecting
various communities or relatively large numbers of co-workers have been
reported. Clusters of CFS cases are unusual, however, and it is not
generally thought that people with CFS need to be isolated in any way. The
clinical and laboratory findings of sporadic versus epidemic cases have yet
to be compared.
While the typical patient seeking medical care for CFS is a white woman in
her thirties, patients of all ages (including the very young and very old),
both sexes, many races, and all socioeconomic groups have been affected. CDC
and NIAID-sponsored researchers have studies under way to try to estimate the
prevalence of this disorder.
Page 3
Historical Perspective
Although interest in this illness has grown tremendously since the mid-1980's
CFS does not appear to be a new disorder. It closely resembles neurasthenia
or neurocirculatory asthenia, diagnoses commonly made in the late 19th and
early 20th centuries. As stated earlier, small epidemics of a very similar
illness (most often called myalgic encephalomyelitis, or ME) have been
described in the medical literature for at least 60 years. Furthermore, case
reports describing similar illnesses date back several centuries. These
sporadic cases of fatigue syndromes have often been linked to bacterial,
viral, or protozoal infections (for example, brucellosis and influenza). But
fatigue syndromes also appear outside the setting of an infectious illness.
Several recent studies indicate that the rheumatologic disorder called
fibrositis or fibromyalgia, first
...........................................................
Febricula, Vapors
##################
Neurasthenia
#######################
Da Costa's (Effort) Syndrome
#################
Chronic Brucellosis
############
Hypoglycemia
###############
Myalgic Encephalomyelitis,
Epidemic Neuromyasthenia
##############
Total Allergy Syndrome
############
Chronic Mononucleosis, Chronic EBV
##############
Chronic Candidiasis
#######
Postviral Fatigue Syndrome
######
Chronic Fatigue Syndrome
###
|_________|_________|_________|________
1800 1850 1900 1950
Timeline graph from 1800 to the present of other diseases with symptoms very
similar to CFS.
Page 4
described in the 19th century, is very similar to CFS. The average age of
the patient with fibrositis is a bit older, however, and soft tissue pain is
a more prominent symptom in this illness.
In the early 1980's, several studies indicated that antibody levels to one
virus, Epstein-Barr virus (EBV), were somewhat higher in patients with CFS
than in healthy individuals. It is important to put this observation in
context. EBV infection is extremely common: approximately 90 percent of
American adults have been infected, and they harbor a lifelong infection
thereafter. In most people the virus remains dormant. Antibody studies
indicate that EBV may be reactivated - i.e., replicating itself - more often
in patients with CFS than in healthy individuals. But the difference is not
striking. Moreover, as mentioned earlier, evidence shows that several other
viruses may also be reactivated in CFS. Therefore, investigators believe
that there is no proof that EBV causes CFS, at least in most patients.
Clinical Picture
A hallmark of CFS is the sudden onset of the illness, typically with flu-like
symptoms. In contrast to the usual flu-like illness, however, the symptoms
of CFS do not fully resolve; they persist chronically, or wax and wane
frequently, accompanied by debilitating fatigue and malaise.
In a few cases, CFS seems to follow from a bout of classic acute infectious
mononucleosis rather than from a nonspecific flu-like illness. In these
cases, EBV - the cause of most cases of acute mononucleosis - may play a role
in the pathogenesis of CFS.
Clearly some CFS symptoms - headache, myalgia, sleep disorder, difficulty
concentrating - could be secondary symptoms of a primary affective disorder.
However, other symptoms such as pharyngitis, fever,
Page 5
adenopathy, and arthralgias suggest a different underlying process.
Many patients have a history of allergies years before the onset of CFS, and
occasionally allergic symptoms worsen after these patients become ill.
Allergies are so prevalent in CFS patients that it is important to
differentiate those symptoms that are allergy-related and thus amenable to
treatment.
The course of CFS varies greatly, with symptoms lasting anywhere from many
months to many years. Symptoms typical of CFS are often seen for short
periods of time; but these symptoms must persist for at least 6 months,
according to the current CDC definition, to entertain a diagnosis of CFS.
Fortunately, CFS is not a progressive disease: usually the symptoms are most
severe in the first year of illness. Systematic studies are under way to
better define the prognosis.
Evaluation of Patients
The patient with the complaint of chronic fatigue that is interfering with
his or her life must be taken seriously.
CFS symptoms overlap with those of many well-recognized illnesses. For
example, Lyme borreliosis, mild systemic lupus erythmatosus (SLE), and early
or mild multiple sclerosis (MS) are among the numerous disorders that
resemble CFS. A history of potential tick exposure, the typical Lyme rash
(erythema chronicum migrans), and antibodies to the Lyme spirochete suggest
the diagnosis of Lyme borreliosis. In both SLE and MS, debilitating chronic
fatigue can be more prominent than rheumatologic or neurologic symptoms.
Psychiatric illnesses that most resemble CFS include major depressive
episode, panic disorder, generalized anxiety disorder, and somatization
disorder. It remains unresolved whether
Page 6
prior or current depressive episodes should exclude a diagnosis of CFS.
Although infectious agents can trigger the syndrome, the diagnosis of CFS
currently is one of exclusion. The Appendix lists several illnesses that
must be considered and "ruled out" when first evaluating a patient with
chronic fatigue. This list is a useful guide but should not be thought of as
exhaustive.
The patient's medical history -- particularly his or her potential
epidemiologic exposures -- and physical examination will help determine the
need for various laboratory tests. A reasonable initial laboratory workup
would include a urinalysis, complete blood count and differential count,
chemistry panel, thyroid function test (a TSH test may be sufficient),
erythrocyte sedimentation rate, anti-nuclear antibodies, and rheumatoid
factor. Significantly abnormal results on any of these tests should prompt
consideration of alternative diagnoses. It is prudent for physicians today
to also consider the possibility of infection with the human immunodeficiency
virus. Subsequent workup should be guided by the clinical picture and may
necessitate a chest X-ray, an electrocardiogram, an Ig level, a tuberculin
skin test, and serum cortisol determinations, among other tests.
Immunologic Features
Many different immunologic findings have been described in patients with CFS,
but no single immunologic disturbance has yet been identified as typical of
the syndrome. Those disturbances observed include depressed natural killer
(NK) cell activity, elevated viral antibody titers, and circulating immune
complexes. These findings indicate general differences between patient
populations
Page 7
and control groups, but none is specific for CFS or abnormal in all CFS
patients. Immunologic changes like these are often associated with
infections and other stressful processes.
Neuropsychologic Features
As mentioned earlier, many patients with CFS also meet diagnostic criteria
for depression or anxiety disorders at presentation. It remains unclear
whether a higher than normal frequency of psychiatric disorders in this
patient group also exists in the years prior to the onset of CFS. On the
other hand, psychiatric evaluations fail to identify any psychiatric
disorders in some patients. Because subtle psychiatric problems can be
difficult to recognize, a consult with a psychiatrist or psychologist may
benefit the evaluation of some patients.
Many people with CFS have neurologic symptoms, including paresthesias,
disequilibrium, and visual blurring. A few patients who are otherwise
identical to the larger group have had more dramatic acute and transient
neurologic events, such as primary seizures, periods of severe visual
impairment, and periods of paresis. These few patients show no evidence of
any well-recognized neurologic disorder such as MS. Patients with these more
dramatic symptoms warrant a more intensive neurologic workup.
One study found that people with CFS have a subtle deficiency of the steroid
hormone cortisol. Because cortisol is a potent suppressor of immune
responses, this finding provides an alternative explanation for some of the
immune findings in the syndrome.
Preliminary research indicates that some patients with CFS demonstrate
punctate areas of high signal in the sub-cortical white matter on magnetic
resonance imaging scans of the brain. Studies are under way to
Page 8
determine if these abnormalities are found more frequently in people with CFS
than in healthy individuals. For many patients, the cognitive impairment
they experience is one of the most disconcerting symptoms. It is usually
characterized as an inability to concentrate, unusual absent-mindedness, and
difficulty with word finding. CFS patients do not exhibit gross dementia.
Neuropsychological testing is being conducted to better define the presence,
nature, and severity of cognitive impairment in patients with CFS.
Etiologic Theories
Several theories have been postulated as to the etiology of CFS. Most
investigators currently believe that no single etiologic agent will prove to
be the cause of all cases. Many investigators believe that the illness
involves a constant antigenic challenge to the immune system and, as a
consequence, a constant immunologic response to that challenge. One popular
theory, which has experimental support, suggests that elevated levels of
cytokines (e.g., interleukin-1, interleukin-2, various interferons) are
generated by an immune system that is doing battle against antigens that it
perceives to be foreign. The flu-like symptoms associated with many common
infections are known to be caused by cytokines. Moreover, when these
cytokines are administered for therapeutic purposes, such as the use of
interleukin-2 or interferon in cancer therapy, many flu-like symptoms occur.
Preliminary evidence suggests that several latent viruses may be actively
replicating more often in CFS patients than in healthy control subjects.
Antibody levels are higher in patients (indirect evidence of active
infection); viral antigen is found more commonly; or there is direct evidence
that the
Page 9
virus is replicating in cells that it commonly infects, such as lymphocytes.
Thus far, those viruses that show some evidence of more frequent active
infection are several members of the herpesvirus family -- EBV,
cytomegalovirus, herpes simplex viruses 1 and 2, and human herpesvirus 6 --
and of the enterovirus family -- coxsackievirus and echovirus.
If subsequent studies confirm that several viruses are active more often in
people with CFS than in healthy individuals, it will then need to be
determined if this activity is a primary or secondary event. Because the
viral agents thus far identified typically infect people in childhood, and
since most patients with CFS are young adults, most investigators believe
reactivation of these viruses is probably secondary to some immunologic
disturbance. If viral activation is indeed a secondary event, it will need
to be determined if it is merely an epiphenomenon, having nothing to do with
the reason the patient feels sick, or whether the viral activation - even if
secondary -- contributes to the symptoms.
Patient Management
CFS is debilitating in all patients, disabling in some, but apparently not
progressive or fatal. The debility and disability stem from a combination of
symptoms such as fatigue, arthralgias, or cognitive impairment, and in some
patients from associated depression. The patients need both symptomatic
treatment and emotional support. It should be noted, however, that some
patients get better all by themselves.
It is vitally important for the physician to be the patient's advocate. In
the absence of any proven treatments, empiric therapies should be tried. At
the same time, patients need to be kept from using exotic, untested remedies
that may hurt them. Physicians also need to be on the lookout for other
medical
Page 10
problems, and to avoid the danger of interpreting every new sign or symptom
as a manifestation of CFS.
For many patients, it is important to slow the pace of their lives and to
avoid situations that are physically or psychologically stressful.
Counseling for both the patient and his or her family benefits their
adjustment to this chronic illness. It is important for them to realize that
no definitive diagnostic or therapeutic approaches exist. Neither has a
specific nutritional program proved beneficial, though a balanced diet and
rest enhance well-being. Some patients benefit from a graduated program of
exercise. At a minimum, patients should be encouraged to maintain physical
conditioning -- in some cases through a sustained program of physical therapy
-- at whatever level of activity they can manage. Abrupt resumption of
vigorous exercise should be avoided, however, because this can exacerbate
symptoms.
Symptomatic treatment can be quite helpful. Non-steroidal anti-inflammatory
drugs may benefit the myalgias, arthralgias, headaches, or fever associated
with the illness. Nonsedating antihistamines may help relieve any prominent
allergic symptoms.
Very few randomized, controlled clinical drug trials for CFS have been
conducted. One such trial found the antiviral drug acyclovir to be no better
than a placebo treatment. In fact, more than 40 percent of patients on
placebo reported improvement.
Several empiric therapies have been tried for CFS. Some investigators have
administered intramuscular or intravenous gammaglobulin, particularly to
those patients who, unlike most patients with CFS, have low levels of
immunoglobulins. There are conflicting claims regarding the efficacy of this
form of therapy -- one trial found some benefit, the other none.
Page 11
Several 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 (an illness similar to CFS), tricyclics
are widely prescribed for CFS patients. Anecdotal experience with tricyclics
has generally been positive. Some investigators believe that the tricyclics
act by improving the quality of sleep. Other types of antidepressants have
also been tried with some success. CFS patients often report that
antidepressants exacerbate their fatigue, however, especially when given in
therapeutic doses. 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, fluoxetine, and MAO inhibitors.
In brief, no strict recipe for treating CFS exists, and sometimes 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 alternatives and appreciate the difficulty in assessing
their benefit in CFS.
Conclusion
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, the immune system, and 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, physicians don't
have all the answers. But in treating people with CFS, they can draw on
practices that have always made medicine a valued art: exclude alternative
problems, ameliorate symptoms, and offer guidance with compassion.
Page 12
Appendix
Research Case Criteria for the
Chronic Fatigue Syndrome*
A case of chronic fatigue syndrome must fulfill major criteria 1 and 2 and
the following minor criteria: 6 or more of the 11 symptom criteria and 2 or
more of the 3 physical criteria; or 8 or more of the 11 symptom criteria.
Major Criteria
1. New onset of persistent or relapsing, debilitating fatigue or easy
fatigability in a person who has no previous history of similar symptoms,
that does not resolve with bedrest, and that is severe enough to reduce or
impair average daily activity below 50% of the patient's premorbid activity
level for a period of at least 6 months.
2. Other clinical conditions that may produce similar symptoms must be
excluded by thorough evaluation, based on history, physical examination, and
appropriate laboratory findings. These conditions include malignancy;
autoimmune disease; localized infection (such as occult abscess); chronic or
subacute bacterial disease (such as endocarditis, Lyme disease, or
tuberculosis), fungal disease (such as histoplasmosis, blastomycosis, or
coccidioidomycosis), and parasitic disease (such as toxoplasmosis, amebiasis,
giardiasis, or helminthic infestation); disease related to human
immunodeficiency virus (HIV) infection; chronic psychiatric disease, either
newly diagnosed by history (such as endogenous depression; hysterical
personality disorder; anxiety neurosis; schizophrenia; or chronic use of
major tranquilizers, lithium, or antidepressive medications); chronic
inflammatory disease (such
*From Holmes GP, et al. Chronic fatigue syndrome: a working case definition.
Ann. Intern. Med. 1988;108:387-9.
Page 13
as sarcoidosis, Wegener's granulomatosis, or chronic hepatitis);
neuromuscular disease (such as multiple sclerosis or myasthenia gravis);
endocrine disease (such as hypothyroidism, Addison disease, Cushing syndrome,
or diabetes mellitus); drug dependency or abuse (such as alcohol, controlled
prescription drugs, or illicit drugs); side effects of chronic medication or
other toxic agent (such as chemical solvent, pesticide, or heavy metal); or
other known or defined chronic pulmonary, cardiac, gastrointestinal, hepatic,
renal, or hematologic disease.
Specific laboratory tests or clinical measurements are not required to
satisfy the definition of the chronic fatigue syndrome, but the recommended
evaluation includes serial weight measurements (weight change of more than
10% in the absence of dieting suggests other diagnoses); serial morning and
afternoon temperature measurements; complete blood count and differential;
serum electrolytes; glucose; creatinine, blood urea nitrogen; calcium,
phosphorous; total bilirubin, alkaline phosphatase, serum aspartate
aminotransferase; creatine phosphokinase or aldolase; urinalysis;
posteroanterior and lateral chest roentgenograms; detailed personal and
family psychiatric history; erythrocyte sedimentation rate; antinuclear
antibody; thyroid-stimulating hormone level; HIV antibody measurement; and
intermediate-strength purified protein derivative (PPD) skin test with
controls.
If any of the results from these tests are abnormal, the physician should
search for other conditions that may cause such a result. If no such
conditions are detected by a reasonable evaluation, this criterion is
satisfied.
Page 14
Minor criteria
Symptom criteria
To fulfill a symptom criterion, a symptom must have begun at or after the
time of onset of increased fatigability, and must have persisted or recurred
over a period of at least 6 months (individual symptoms may or may not have
occurred simultaneously). Symptoms include:
1. Mild fever -- oral temperature between 37.6 degrees C and 38.6 degrees C,
if measured by the patient -- or chills. (Note: oral temperatures of greater
than 38.6 degrees C are less compatible with chronic fatigue syndrome and
should prompt studies for other causes of illness.)
2. Sore throat.
3. Painful lymph nodes in the anterior or posterior cervical and axillary
distribution.
4. Unexplained generalized muscle weakness.
5. Muscle discomfort or myalgia.
6. Prolonged (24 hours or greater) generalized fatigue after levels of
exercise that would have been easily tolerated in the patient's premorbid
state.
7. Generalized headaches (of a type, severity, or pattern that is different
from headaches the patient may have had in the premorbid state).
8. Migratory arthralgia without joint swelling or redness.
9. Neuropsychologic complaints (one or more of the following: photophobia,
transient visual scotomata, forgetfulness, excessive irritability, confusion,
difficulty thinking, inability to concentrate, depression).
10. Sleep disturbance (hypersomnia or insomnia).
11. Description of the main symptom complex as initially developing over a
few hours to a few days (this is not a true symptom, but may be considered as
equivalent to the above symptoms in meeting the requirements of the case
definition).
Page 15
Physical Criteria
Physical criteria must be documented by a physician on at least two
occasions, at least 1 month apart.
1. Low-grade fever - oral temperature between 37.6 degrees
C and 38.6 degrees C, or rectal temperature between 37.8
degrees C and 38.8 degrees C. (See note under Symptom Criterion 1.)
2. Nonexudative pharyngitis.
3. Palpable or tender anterior or posterior cervical axillary lymph nodes.
(Note: lymph nodes greater than 2 cm in diameter suggest other causes.
Further evaluation is warranted.)
To receive a CFS information packet, contact:
Office of Communications
National Institute of Allergy and
Infectious Diseases
Building 31, Room 7A32
9000 Rockville Pike
Bethesda, MD 20892
(301) 496-5717
National Institute of Allergy
and Infectious Diseases
NIH Publication No. 92-484
May 1992
