 
 
                  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
 

