Chronic Fatigue Syndrome:An Update on Diagnosis in Primary Care

ABSTRACT: The chief characteristic of chronic fatigue syndrome (CFS) is a disabling fatigue that can impair normal daily functioning and/or occupational performance. CFS is considered a 3-stage illness that involves predisposing, precipitating, and perpetuating factors. Abnormalities in the central and autonomic nervous systems, possibly linked to a viral trigger and ongoing immune system dysregulation, may play a role in the pathophysiology of the disorder. Although no laboratory findings are specific for CFS, the pattern of certain laboratory results and clinical presentation can support the diagnosis in patients with cognitive dysfunction in whom other diseases have been excluded as a cause of fatigue. Three conditions characterized by chronic fatigue that should initially be ruled out in the workup are fibromyalgia, hypothyroidism, and Lyme disease.

Key words: chronic fatigue syndrome, symptoms, diagnosis

Chronic fatigue syndrome (CFS) is a distinct disorder characterized by debilitating and often recurrent fatigue that lasts at least 6 months but more frequently lasts for longer periods.^1-3 Patients with CFS experience overall physical, social, and mental impairments and may subsequently qualify for medical disability.³ Because the cause of CFS has not been identified, the diagnosis is usually made after other medical and psychiatric disorders associated with fatigue have been excluded.^2,3 In general, the diagnosis of CFS is made on the basis of the CDC criteria (Table 1).^3,4

Numerous studies have been conducted on the diagnosis and treatment of CFS since I first wrote on this topic for CONSULTANT in 2000.¹ In this 2-part update, I have incorporated the results of these recent studies. Here, in part 1, I focus on the diagnosis of CFS in primary care practice. In a coming issue, I will discuss the treatment of this disorder.

HISTORICAL BACKGROUND
In Europe, myalgic encephalomyelitis is the preferred descriptive term for CFS. Other terms include myalgic encephalopathy, post-viral fatigue syndrome or chronic fatigue, and immune dysfunction syndrome.^1-5 Through the decades, the condition has also been associated with poorly described disease states, such as neurasthenia, Da Costa syndrome (reported after the American Civil War), chronic mononucleosis, and vapors.⁶

Myalgic encephalomyelitis was first reported after outbreaks of viral infections in the 1950s; it is still listed in the World Health Organization’s International Classification of Diseases (G93.3, ICD-10) as a neurological disease.^2,6 The term “post-viral fatigue syndrome” was introduced in the 1980s.

The term “CFS” is currently preferred in the United States and Canada because studies have shown subtle immunological changes in affected patients, such as an elevation in levels of cytotoxic T cells and proinflammatory cytokines and low natural killer cell activity.⁷ Recent research on DNA microarray and gene profiling of patients with CFS suggests these changes result from increased oxidative stress, accelerated apoptosis (programmed cell death), and altered immune regulation.^6-8

I – Chronic Fatigue Syndrome in Children and Adolescents

Chronic fatigue syndrome (CFS) may be one of the most common causes of long-term absence from school in children and adolescents.¹⁹ Although the chief symptoms are similar to those seen in adults, children may have additional symptoms, such as abdominal pain, nausea, and sinus congestion. If you suspect CFS in a child or adolescent with suggestive symptoms, an assessment to exclude other diagnoses is warranted within 6 weeks of the initial presentation.

EPIDEMIOLOGY
Because various studies define CFS differently, data about its prevalence and incidence are difficult to interpret.^1,2,9,10 The condition is most common in persons in their 40s and 50s. In children, the typical age of onset is 13 to 15, but cases can occur in those as young as 5 years (Box I). The condition affects persons of all ages, social classes, and ethnic groups. Overall, the evidence suggests a population prevalence of at least 0.2% to 0.4%. In a primary care setting, it is possible that 40 of every 10,000 patients have CFS.

CFS is 2 to 4 times more common in women than in men and is more frequently reported in the United States and Canada than in the rest of the world.^10,11 However, sex has not been confirmed as a risk factor for CFS, because women may be more likely than men to report their symptoms.

At least 25% of persons who have CFS are unemployed or are receiving disability payments. The CDC has estimated that the average family affected by CFS forgoes almost $20,000 annually in lost earnings and that CFS costs the United States $9.1 billion per year in lost productivity.³

ETIOLOGY
Possible causes. CFS has no clear cause. The following conditions have been proposed as possible causes¹¹:

• Hypoglycemia.
• Viral infection, such as Epstein-Barr virus or human herpesvirus 6 (HHV6) infection.
• Immune system dysfunction.
• Hypothalamus, pituitary, or adrenal gland dysfunction.
• Mild chronic hypotension.
• Peripheral neuropathy.

Although some reports mention that depression, iron deficiency, allergies, thyroid dysfunction, and neuritis are possible causes of CFS, they rather can cause fatigue or may be co-occurring conditions. In most patients with CFS, no serious underlying infection or disease has been found.

A 3-stage illness. A consensus has emerged in considering CFS as a 3-stage illness that involves predisposing, precipitating, and perpetuating factors.¹²

Predisposing factors. Studies of twins suggest that genetic predisposition plays a role in CFS, which may help explain the slightly higher than expected familial incidence.¹³ Profiles in the peripheral blood of patients with CFS and that of age- and sex-matched healthy subjects were conducted using a custom microarray carrying complementary DNA probes for 1467 stress-responsive genes. The genetic profiles identified 12 genes whose messenger RNA levels were changed significantly in CFS patients. Quantitative real-time analysis validated the changes in 9 genes encoding in activated T or natural killer cells, energy regulators, proteasome subunits, putative protein kinase inhibitors, and signal transducers and activators of transcription. The results of these genetic studies suggest that the defined gene cluster (9 genes) may be useful for detecting pathological responses in CFS patients.

Precipitating factors. Many patients with CFS report that their illness followed an infection.^12-16 A wide variety of viral infections-including glandular fever, hepatitis, meningitis, and parvovirus and enterovirus infections-are known to trigger CFS. Nonviral infections such as Q fever (Coxiella burnetii infection) are occasionally implicated as well. Although infections are a common trigger, most current evidence suggests that persistent viral infection is not part of the ongoing pathology. Immunizations, organophosphate pesticides, toxins, and physical trauma have been reported as the principal trigger in a small minority of cases. About 25% of patients with CFS describe a gradual onset of their illness with no obvious precipitating factor.

Perpetuating factors. There is evidence, some of it replicated, to indicate that abnormalities in the central and autonomic nervous systems, possibly linked to a viral trigger and ongoing immune system dysregulation, play a key role in the pathophysiology of CFS.¹⁴

Recently, scientists identified a virus in 68 of 101 patients who had received a diagnosis of CFS. Whether the virus known as xenotropic murine leukemia virus (XMRV) causes the syndrome is still unclear.¹⁷

DIAGNOSTIC CRITERIACDC criteria. The diagnostic criteria for CFS were defined by the CDC in 1988^3,9; these criteria were revised in 2001. they are summarized in Table 1.

The major inclusion criterion is clinically evaluated, unexplained, persistent, or relapsing fatigue that is of new or definite onset, not a result of ongoing exertion, and not alleviated by rest and that results in a substantial reduction in previous levels of occupational, social, or personal activity.

The minor inclusion criterion is the presence of 4 or more of the following symptoms that persist or recur during 6 or more consecutive months of illness and that do not predate the fatigue:

• Self-reported impairment of short-term memory or concentration.
• Sore throat.
• Tender lymph nodes.
• Muscle pain.
• Multi-joint pain without swelling or redness.
• Headaches of a new type, pattern, or severity.
• Unrefreshing and/or interrupted sleep.
• Postexertion malaise lasting more than 24 hours.

Exclusion criteria include the following:

• Active, unresolved, or suspected disease that is likely to cause fatigue.
• Depression with psychotic or melancholic features, bipolar depression (but not uncomplicated major depression).
• Psychotic disorders.
• Dementia.
• Anorexia or bulimia nervosa.
• Alcohol or other substance abuse.
• Severe obesity.

Oxford criteria. The Oxford criteria differ slightly from the CDC criteria in that they emphasize the presence of mental fatigue.^15,16,18,19 The major inclusion criterion is severe disabling fatigue of at least 6 months’ duration that affects both physical and mental functioning and is present more than 50% of the time. Other symptoms, particularly myalgia and sleep and mood disturbances, may be present.

The exclusion criteria are similar to those of the CDC; however, the Oxford criteria do not list substance abuse or severe obesity.

Additional symptoms. Although the symptoms described here are the official diagnostic criteria, many patients with CFS also have a variety of other symptoms, which are listed in Table 2.^15,16,18-20

II – Controversial Laboratory Tests

The following tests, which are often promoted as diagnostic of chronic fatigue syndrome, are generally not indicated^2,6,11-13; they add only an unnecessary burden for patients and primary care clinicians:

 • Extensive immunological testing, which may show low natural killer cell counts; elevated levels of interferon alpha, tumor necrosis factor a, and interleukin-1 and -2; T-cell activation; altered T4:T8 cell ratios; low T-cell suppressor cell (T8) count; fluctuating B- and T-cell counts; antinuclear antibodies; immunoglobulin deficiency; and antithyroid antibodies.

 • Tests for viral infections, such as those caused by cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, and coxsackievirus.

 • Assessments of oxidative stress.

 • Measurement of homocysteine levels.

 • Measurement of C-reactive protein levels.

 • Toxin analysis, including heavy metals, pesticides, and organic chemicals.

 • Measurement of red blood cell magnesium levels.

 • Allergy testing, particularly serological tests for Candida.

EVALUATIONHistory and physical examination. Obtain a detailed history that includes an assessment of predisposing, precipitating, and perpetuating factors; sleep disturbances; and psychosocial stressors.^2-4,10,14 In addition, perform a complete physical examination. The initial examination may reveal the following signs:

• Low blood pressure, particularly orthostatic hypotension.
• Low oral temperatures (less than 36.1°C [97°F]).
• Slightly elevated oral temperatures (but less than 37.7°C [100°F]), which are part of a constellation of persistent flu-like symptoms.
• Tachycardia.
• A positive Romberg sign.

Laboratory studies. These tests can be used to exclude other diseases associated with fatigue.^12-16 The most consistent laboratory abnormality in patients with CFS is an extremely low erythrocyte sedimentation rate (ESR), which approaches zero. Typically, patients with CFS have an ESR of 0 to 3 mm/h. A normal ESR or one that is in the upper reference range suggests another diagnosis.

Thyroid function tests-chiefly, measurement of thyroid-stimulating hormone-are useful in ruling out other disorders that may be associated with fatigue. In addition, consider ordering adrenal tests (with measurement of morning and evening cortisol levels), Lyme titers, and HIV serology.

Results of liver function tests are typically normal in patients with CFS. Increased levels of serum transaminases, alkaline phosphatase, or lactic dehydrogenase should prompt a search for another disorder. Urinalysis findings are usually unremarkable.

The white blood cell count in patients with CFS is also typically normal. Leukopenia, leukocytosis, or an abnormal cell differential count indicates a diagnosis other than CFS.

Results of serum protein electrophoresis are normal in patients with CFS, but this test may be used to rule out other diseases that cause fatigue, including lymphoma and myeloma.

Patients with CFS may have 2 or 3 of the following abnormalities:

• Elevated IgM/IgG coxsackievirus B titer.
• Elevated IgM/IgG HHV6 titer.
• Elevated IgM/IgG Chlamydia pneumoniae titer.
• Decreased natural killer cells, either the percentage or their activity.

Although no laboratory abnormality is specific for CFS, the pattern of findings can support the diagnosis in patients with cognitive dysfunction in whom other diseases have been excluded as a cause of fatigue. Controversial laboratory tests that are not indicated in the workup of CFS are listed in Box II.

Imaging studies. CT or MRI scanning of the brain is useful for ruling out CNS disorders in patients with otherwise unexplained CNS symptoms. Results of CT and MRI scans may be normal in patients with CFS. Positron emission tomography scans may show hypoperfusion in the frontoparietal/temporal region.^12-16 The results of CNS imaging studies are not specific for CFS and are thus used to rule out other conditions rather than to diagnose CFS.

DIFFERENTIAL DIAGNOSIS
Other disorders that are associated with fatigue must be distinguished from CFS.^3,9-12 The differential diagnosis is listed in Table 3. Conditions that are characterized by chronic fatigue should initially be ruled out; these include fibromyalgia, hypothyroidism, and Lyme disease. In veterans who served in Operation Desert Shield/Desert Storm, Gulf War syndrome should be excluded.

Fibromyalgia. The American College of Rheumatology guidelines recommend testing 18 points of body tenderness; the presence of at least 11 of the points may indicate fibromyalgia.²⁰ Although many clinicians find these guidelines controversial, trigger points are characteristic of fibromyalgia; they are not present in patients with CFS.

Most patients with fibromyalgia are female and have a chief complaint of “hurting all over, all the time.” The constant pain in those with fibromyalgia is usually described as burning, aching, and associated with soreness. The location of the pain migrates, and its intensity varies. Many patients report only a single painful area, such as the low back or neck. Most patients also have morning stiffness of variable duration. In addition, concurrent restless legs syndrome is common.

Hypothyroidism. This condition typically manifests as a general slowing in physical and mental activity, but in some patients it may be asymptomatic. Classic manifestations include cold intolerance, puffiness, decreased sweating, and coarse skin; however, symptoms and signs are often subtle and are neither sensitive nor specific.²¹ Hypothyroidism can be differentiated from CFS on the basis of clinical suspicion, and the diagnosis can be confirmed by laboratory testing.

Lyme disease. This disease can be differentiated from CFS in various ways. Patients who live in areas with endemic Lyme disease may have elevated IgG Lyme titers. Some patients have neuroborreliosis; this diagnosis is made on the basis of simultaneous measurement of cerebrospinal fluid (CSF) and serum IgM and IgG Lyme titers. CSF titers that are higher than serum titers indicate neuroborreliosis. Acute Lyme disease usually has a neurological component, but chronic neuroborreliosis is distinctly uncommon. Patients with chronic neuroborreliosis do not have the same cognitive defects as patients with CFS and usually do not present with fatigue as their chief complaint.^18,22

Gulf War syndrome. Gulf War syndrome, or Gulf War illness, has been used to describe a constellation of chronic signs and symptoms reported by US, British, Canadian, Czech, Danish, Saudi, Egyptian, Australian, and other Coalition Armed Forces who were deployed in 1990 to 1991 during Operation Desert Shield/Desert Storm. It is estimated that 1 in 4 of the 697,000 US Gulf War veterans has this condition.²³

The syndrome is characterized by disabling fatigue, intermittent fever, night sweats, arthralgia, myalgia, headache, rashes, intermittent diarrhea, abdominal bloating, chronic bronchitis, photophobia, transient visual scotomata, short-term memory impairment, confusion, irritability, and depression. The symptoms are not localized, and the signs and routine laboratory test results are not consistent with a single, specific disease. The incidence of amyotrophic lateral sclerosis may also be higher in Gulf War veterans. In addition, an increase in birth defects and stillbirths, as well as in cases of motor neuron disease and leukemia, has been reported among children of these soldiers.²³

References:

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Acknowledgments: The author thanks the VA Medical Center director, Mr Al Perry, FACHE, for his leadership and the chief of staff, Dr Wessel Meyer, for his support; Drs Robert Hierholzer, Nestor Manzano, Scott Ahles, and Craig C. Campbell, for their clinical guidance; Dr Avak A. Howsepian for his constructive criticism; Matthew Battista, PhD, and Leonard Williams, PA, for their encouragement; and Ms Ruth A. Cowell for her secretarial assistance.