Chronic Fatigue Syndrome:

Evaluation and Treatment

TIMOTHY CRAIG, D.O., and SUJANI KAKUMANU
Pennsylvania State University College of Medicine, Hershey, Pennsylvania

Severe fatigue is a common complaint among patients. Often, the fatigue is transient
or can be attributed to a definable organic illness. Some patients present with persis- O A patient infor-
tent and disabling fatigue, but show no abnormalities on physical examination or mation handout on
chronic fatigue syn-
screening laboratory tests. In these cases, the diagnosis of chronic fatigue syndrome
drome, written by
(CFS) should be considered. CFS is characterized by debilitating fatigue with associated the authors of this
myalgias, tender lymph nodes, arthralgias, chills, feverish feelings, and postexertional article, is provided
malaise. Diagnosis of CFS is primarily by exclusion with no definitive laboratory test or on page 1095.
physical findings. Medical research continues to examine the many possible etiologic
agents for CFS (infectious, immunologic, neurologic, and psychiatric), but the answer
remains elusive. It is known that CFS is a heterogeneous disorder possibly involving an
interaction of biologic systems. Similarities with fibromyalgia exist and concomitant ill-
nesses include irritable bowel syndrome, depression, and headaches. Therefore, treat-
ment of CFS may be variable and should be tailored to each patient. Therapy should
include exercise, diet, good sleep hygiene, antidepressants, and other medications,
depending on the patient’s presentation. (Am Fam Physician 2002;65:1083-90,1095.
Copyright© 2002 American Academy of Family Physicians.)

C
hronic fatigue syndrome Other disorders, such as fibromyalgia, have
(CFS), also referred to as overlapping symptoms with CFS, suggesting
chronic fatigue immune defi- that both diseases may share common physi-
ciency syndrome, is a disabling ologic abnormalities.
illness characterized by persis- Chronic fatigue syndrome affects both gen-
tent fatigue accompanied by rheumatologic, ders, all racial, ethnic, and socioeconomic
cognitive, and infectious-appearing symp- populations, and can begin as early as five
toms. Despite intense medical research, there years of age.1,2 Although previous reports
is no known cause for CFS, but it appears to showed a predominance of CFS in well-edu-
be a heterogeneous disorder which affects cated, white females between 20 and 50 years
multiple systems, including hormonal, neu- of age, these findings may be skewed by study
rologic, and immunologic. Because there are populations that were selected from patients
no specific diagnostic tests or physical find- who sought medical care for the disorder.1,2
ings for CFS, diagnosis requires knowledge of Furthermore, the diagnostic ambiguity sur-
possible symptoms and a method of exclu- rounding CFS invariably leads to imprecise
sion. CFS is likely a spectrum of illnesses and inconsistent epidemiologic statistics.
sharing a common pathogenesis with varying
degrees of fatigue and associated symptoms. Clinical Presentation
The Centers for Disease Control and Preven-
tion’s criteria for diagnosis of CFS (Table 1)1
The Centers for Disease Control and Prevention’s criteria for require patients to present with severe fatigue
lasting for at least six consecutive months,
diagnosis of chronic fatigue syndrome require the patient to
have no definable organic disease, and experi-
present with severe fatigue lasting at least six consecutive ence associated physical symptoms. Because
months, have no definable organic disease, and experience fatigue is a common symptom in many dis-
associated physical symptoms. eases, a wide differential diagnosis (Table 2)3
needs to be excluded. A complete history

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 should be taken and a physical examination ple, serologic and neurologic analyses for
should be performed on all patients to exclude Lyme disease or multiple sclerosis need only
secondary fatigue caused by psychiatric ill- be conducted if the patient presents with
ness, substance abuse, or medical conditions appropriate symptoms.
that are known to cause persistent fatigue
(Figure 1).3-6 Laboratory tests should be lim- Etiology
ited to complete blood cell counts and tests INFECTIOUS
specific for the patient’s symptoms. For exam- Many patients with CFS attribute the onset
of their illness to an acute influenza-like infec-
tion, and, subsequently, the role of viruses as
possible causative agents for CFS has been
TABLE 1 intensively studied. In particular, an early
Current CDC Criteria for Diagnosis of Chronic Fatigue Syndrome study7 reported that patients with CFS pre-
sented with symptoms similar to acute infec-
tious mononucleosis and were found to have
high titers of IgG antibodies to Epstein-Barr
virus (EBV). However, subsequent research8
refuted a correlation between titers of EBV
The rightsholder did not antibodies and severity of symptoms in CFS,
grant rights to reproduce and showed that patients with CFS did not
this item in electronic have significantly higher titers to EBV com-
pared with healthy control subjects.
media. For the missing Although a number of other viral pathogens
item, see the original print (such as the Coxsackie virus, human herpes
version of this publication. virus 6, cytomegalovirus, measles, and the
human T-cell lymphotropic virus [HTLV-II])
have also been implicated as etiologic agents for
CFS, there is no consistent or conclusive data to
suggest any causal relationships.9-11 It is now
believed that CFS is not specific to one patho-
genic agent but could be a state of chronic
immune activation, possibly of polyclonal
activity of B-lymphocytes, initiated by a virus.
Patients with CFS can show different lympho-
cyte and cytokine profiles depending on the
nature of their illness and its time of onset.

IMMUNOLOGIC
Many of the symptoms seen in patients
with CFS, such as disabling lethargy, myalgias,
and cognitive impairment, are similar to the
effects observed with high dosage treatments
of cytokines including interleukin-2 and alpha
interferon.12,13 Given that CFS may be an ill-
ness of immune dysregulation, numerous
studies14-18 have attempted to identify abnor-
malities in circulating immune complexes,

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 Chronic Fatigue Syndrome

TABLE 2
Differential Diagnosis for Chronic Fatigue Syndrome

Infectious Hematologic
Chronic Epstein-Barr virus Anemia
Influenza Lymphoma
HIV infection Occult malignancy
Other viral infections (HHV-6, retroviruses, Exclusionary tests: history, physical examination,
enteroviruses) screening laboratory tests, peripheral blood
Tuberculosis smears
Lyme disease
Rheumatologic
Exclusionary tests: history, physical, screening Fibromyalgia
laboratory tests, and serology if clinically indicated Sjögren’s syndrome
Neuroendocrine Polymyalgia rheumatica
Hypothyroidism Giant cell arteritis
Hyperthyroidism Polymyositis
Addison’s disease Dermatomyositis
Adrenal insufficiency Exclusionary tests: history, physical examination,
Cushing’s disease screening laboratory tests if clinically indicated
Diabetes
Other
Exclusionary tests: history, physical examination, Nasal obstruction from allergies, sinusitis, anatomic
screening laboratory tests; consider hormone and obstruction
stimulation and/or suppression tests (e.g., TSH, Chronic illness (CHF, renal, hepatic, pulmonary dis-
T3 suppression test, ACTH, cortrosyn stimulation, ease, autoimmune)
dexamethasone suppression, urinary free cortisol, Pharmacologic side effects (e.g., beta blockers,
glucose) if clinically indicated. antihistamines)
Psychiatric Alcohol or substance abuse
Bipolar affective disorder Heavy metal exposure and toxicity (e.g., lead)
Schizophrenia Body weight fluctuation (severe obesity or marked
Delusional disorders weight loss)
Dementia Exclusionary tests: history, physical examination,
Anorexia nervosa screening laboratory tests, allergy testing and
Bulimia nervosa toxicology screens if indicated
Exclusionary tests: history, physical examination,
mental status examination, screening laboratory
tests if clinically indicated
Neuropsychologic
Obstructive sleep syndromes (sleep apnea, narcolepsy)
Multiple sclerosis
Parkinsonism
Exclusionary tests: history, physical examination,
mental status tests, screening laboratory tests
and imaging studies if indicated

HIV = human immunodeficiency virus; HHV-6 = human herpesvirus type 6; TSH = thyrotropin-stimulating hor-
mone; T3 = triiodothyonine; ACTH = adrenocorticotropic hormone; CHF = congestive heart failure.
Adapted with permission from Cho WK, Stollerman GH. Chronic fatigue syndrome. Hosp Pract (Off Ed) 1992;
27:221-4, 227-30, 233-6.

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 increased interferon activity, cytokine levels, event, such as a viral infection, could produce
lymphocyte cell markers, or natural killer a cascade of immune and neuroendocrine
cells. However, the data are inconsistent.14-18 abnormalities. The varied nature of illness
Nevertheless, the implication of immune dis- onset and infectious agents could produce dif-
order in patients with CFS is supported by ferent immune profiles among patients with
reports that lymphocyte markers (including CFS. Although the data supporting this
CD4+ cell counts and adhesion molecules) hypothesis remain speculative, this finding
may be increased in patients with CFS. These suggests that at least a subset of CFS patients
findings, however, have been inconsistent may have immune dysregulation.
among studies.17,19
In a recent study,18 patients with CFS AUTONOMIC NERVOUS SYSTEM
showed normal natural killer cell numbers but Evidence supports that CFS may be an ill-
low natural killer activity. Researchers sug- ness mediated by the central nervous system.
gested that this is a result of an inability to Patients with chronic fatigue syndrome pre-
replenish activated natural killer cells.18 This sent with cognitive deficits in concentration,
hypothesis may explain how a triggering attention, and short-term memory. More

Evaluation for Chronic Fatigue Syndrome

History and physical examination Exclude CFS if another

Establish prolonged and unexplained fatigue. condition exists.
Evaluate mental status; personal and family psychiatric history.
Exclude other diagnostic possibilities.

Laboratory tests Exclude CFS if another

Screen to exclude other diagnoses: condition exists.
Serial weights, serial A.M. and P.M. temperatures, CBC, ESR,
electrolytes, glucose, ALT, total protein, albumin, globulin,
alkaline phosphatase, BUN, creatinine, creatine kinase, Ca,
PO4, TSH, and UA
Additional tests to support exclusion: serologies (Lyme disease,
hepatitis B and C screen, HIV, ANA), PPD skin tests

If fatigue persists for at least six months, evaluate for Classify as idiopathic chronic
associated symptoms. fatigue if associated
Four or more of the following symptoms are present: symptoms are not present.
myalgias, arthralgias, sore throat, lymphadenopathy,
headaches, postexertional malaise, impaired memory
and/or concentration.

FIGURE 1. Algorithm for the evaluation of a patient for chronic fatigue syndrome. (CFS = chronic
fatigue syndrome; CBC = complete blood cell count; ESR = erythrocyte sedimentation rate;
ALT = alanine aminotransferase; BUN = blood urea nitrogen; Ca = cancer; PO4 = phosphate radi-
cal; TSH = thyrotropin-stimulating hormone; UA = urinalysis; HIV = human immunodeficiency
virus; ANA = antinuclear antibodies; PPD = purified protein derivative)
Information from references 3 through 6.

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 Chronic Fatigue Syndrome

specifically, persons with neurally mediated

hypotension experience periods of light-head- Studies have shown that two thirds of patients with CFS
edness, syncope, and fatigue after periods of have signs of major depressive illness and one half of all
orthostatic stress (erect posture). Studies19,20
patients with CFS have experienced at least one episode of
investigating this phenomenon as a cause of
CFS have not produced consistent results. major depression.
When treatments specific to neurally medi-
ated hypotension were administered to
patients with CFS, the results were inconclu- clinical depression. This occurrence is rein-
sive. The use of fludrocortisone (Florinef) forced by reports that patients with CFS are
alone had no beneficial effect. Although use of more prone to depression than healthy sub-
low-dose hydrocortisone resulted in a slight jects and are often excessively emotional.26
improvement of symptoms, the risk associated Studies have shown that two thirds of patients
with chronic use of corticosteroids outweighed with CFS have signs of major depressive ill-
the therapeutic benefits.21,22 Other therapeutic ness and one half of all patients with CFS have
interventions that have been suggested experienced at least one episode of major
include: salt loading to increase vascular vol- depression. Although there is some overlap in
ume by increasing dietary sodium chloride; symptoms presented by patients with CFS and
beta blockers to inhibit the epinephrine rush those with depression, patients with CFS also
that accompanies hypotension; and alpha show symptoms that are not typical of clinical
adrenergics to increase vascular resistance.19-22 depression, such as sore throat, lym-
Diagnostic imaging studies have also pro- phadenopathy, and postexertional malaise.
vided preliminary data to suggest that patients Patients with CFS lack feelings of anhedonia,
with CFS may have neurologic abnormalities. guilt, and decreased motivation classically
Magnetic resonance imaging has shown the seen in patients with depression.26,27
presence of cerebral lesions in white matter,
predominantly in the frontal lobes.23 Regional MUSCULAR
cerebral flow studies24 using single photon Patients with CFS often complain of myal-
emission computed tomography analysis have gias and arthralgias, but exhibit no diagnostic
shown impaired regional cerebral blood flow signs of musculoskeletal disorder. A study28
in patients with CFS compared with healthy investigating muscular function in patients
control subjects. A later study25 using positron with CFS reported reduced work capacity
emission tomography analysis compared compared with healthy control subjects. There
patients who had CFS and no history of have also been reports29,30 that patients with
depression with clinically depressed patients CFS show decreased cognitive performance
who had no history of CFS; the study found after maximal physical activity compared with
altered frontal cortical metabolism in both healthy control subjects.
patients with CFS and patients with depres-
sion compared with healthy control subjects. ALLERGIC
Whether the functional impairment in A recent study31 suggested that patients with
patients with CFS is caused by a concurrent CFS have a higher occurrence of allergies com-
psychiatric illness is still inconclusive. pared with normal populations. Although it
has been reported that the increased incidence
PSYCHIATRIC of atopic illness among patients with CFS is the
Because CFS lacks definitive organic causes, result of an increased use of allergy tests on this
it is often dismissed by physicians as either a population by physicians,32 most studies show
psychosomatic illness or a manifestation of that patients with CFS are more susceptible to

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 in patients with CFS. Exacerbations of allergic
Given the ambiguity surrounding CFS, the current suggested disease, such as rhinitis, could affect cytokine
management includes exercise, optimal diet, appropriate levels and natural killer cell function, thereby
producing the abnormal immunologic and
sleep hygiene, low-dose tricyclic antidepressants and/or a
endocrine profiles seen in patients with CFS.
selected serotonin reuptake inhibitor, combined with cogni- More recent data suggest that the rhinitis in
tive-behavior therapy. CFS is not allergy induced but is instead
thought to be secondary to the neuroen-
docrine disorders commonly found in CFS.35
atopic disease. Given the association between
CFS and allergies, there is a strong possibility Treatment
that allergies are essential to the pathology of Because there is no known cause of CFS,
CFS. Not only do patients with CFS present current treatment remains symptomatic with
with positive skin tests to allergens, but they a focus on management rather than cure.
also have elevated levels of circulating Numerous clinical trials of pharmacologic
eosinophilic cationic proteins compared with agents have been conducted but no definitive
healthy subjects.33 Rhinitis is a common atopic therapeutic benefit has been identified.
illness that affects 20 to 30 percent of the pop- Tricyclic antidepressants and selective sero-
ulation, and allergic rhinitis has been shown to tonin reuptake inhibitors (SSRIs) are com-
disrupt sleep.34 It is not yet known whether this mon therapy for patients with CFS. Tricyclic
disrupted sleep pattern contributes to the antidepressants have proven to be effective in
pathology of CFS. reducing clinical depression and improving
It is generally accepted that the neuroen- sleep patterns and are reportedly beneficial for
docrine-immunologic network plays a role in patients with chronic fatigue. Although clini-
the pathogenesis of CFS. Therefore, it is rea- cal trials29 of tricyclic antidepressants have not
sonable to hypothesize that allergens, similar produced definitive results, it is believed that
to infectious agents, could serve as a triggering along with their antidepressive effect they also
event for the many symptoms specific to CFS. promote stage 4, nonrapid eye movement
Given the interactions among the hypothala- sleep and stimulate the descending inhibitory
mic-pituitary-adrenal axis, neural and pathways of pain control. While anecdotal evi-
immune system, an allergen, similar to an dence and small noncontrolled studies sup-
infectious agent, can initiate a variety of port the use of the SSRIs fluoxetine (Prozac)
symptoms along with severe fatigue, as is seen and bupropion (Wellbutrin), placebo-con-
trolled trials of these drugs have not signifi-
cantly benefited patients with CFS.36,37 A
recent investigation34 of nicotinamide-ade-
The Authors
nine dinucleotide (NADH) therapy reported
TIMOTHY J. CRAIG, D.O., is associate professor of medicine, pediatrics, and graduate promising results. The authors of this report34
studies at Pennsylvania State University College of Medicine, Milton S. Hershey Med-
ical Center, Hershey. Dr. Craig graduated from the New York College of Osteopathic stipulated that a decreased adenosine triphos-
Medicine, Old Westburg, N.Y., completed a rotating internship and medicine training phate level, when alleviated by NADH ther-
at San Diego Naval Hospital, and received training in allergy and immunology at Wal- apy, improves muscle atrophy and neuroen-
ter Reed Medical Center, Washington, D.C.
docrine abnormalities.
SUJANI KAKUMANU is currently a third-year medical student at the Pennsylvania State Reports of subtle hypocortisolism in
University College of Medicine. She completed a bachelor’s degree in psychology at
Cornell University, Ithaca, N.Y. patients with CFS has spurred interest in
treatment with mineralocorticoids and corti-
Address correspondence to Timothy J. Craig, D.O., Department of Medicine, Pennsylva-
nia State University College of Medicine, Hershey Medical Center, 500 University Ave., costeroids. In a randomized control study38 of
Hershey, PA 17033 (e-mail: [email protected]). Reprints are not available from the authors. 32 patients, researchers successfully demon-

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 Chronic Fatigue Syndrome

strated a response to low-dose hydrocortisone tinues, future researchers may be drawn

(five to 10 mg daily). Fatigue was improved toward a holistic approach to CFS, specifically
and disability was reduced without significant as an interaction among neural, endocrine,
short-term adverse events.38 and immune systems. Symptoms and treat-
Cognitive behavior therapy is a psychother- ment may differ from patient to patient
apeutic treatment postulating that patients depending on illness onset and genetic predis-
with CFS may perceive their physical symp- position. Treatment of concomitant disorders
toms as insurmountable, thereby precluding such as migraine headache, irritable bowel
any hope for recovery. Cognitive behavior syndrome, depression, panic disorder, and
therapy examines both the patient’s cognition fibromyalgia may significantly improve the
and behavior to identify unhealthy coping quality of life of the affected patient.6 Future
skills. Recent studies have produced promis- technologic advances in neuroimaging, geno-
ing results. Other psychologic treatments such type profiling, immune assays, and pharma-
as support groups and a positive physician- cologic therapy may bring greater consistency
patient relationship have proven to be benefi- to scientific research and the possibility of
cial in the long-term management of CFS.39 improved therapy for patients with CFS.
The role of exercise in treating patients with
CFS has recently been emphasized. Long-term Funded by a grant from the General Clinical
physical inactivity can lead to physical decon- Research Center of Pennsylvania State University
College of Medicine, Hershey Medical Center, which
ditioning that further complicates the symp-
is supported by the National Institutes of Health.
toms of CFS and has detrimental effects on
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