Clinical manifestations

Presentation and course

The most commonly reported symptoms vary according to source. A Centers for Disease Control study indicates that sore throat, fever, tender lymph nodes, general weakness, and muscle pain are the most frequent symptoms (39), whereas another source reported unrefreshing sleep, muscle pain, postexertion fatigue, thinking or memory impairment, and joint pain as the 5 most prevalent symptoms (33). A third study suggests (in decreasing frequency) fatigue after exercise, poor concentration, forgetfulness, muscle pain, stiff joints, light sensitivity, upset stomach, headaches, sore throats, and breathlessness are the most frequent symptoms (29). Despite the grouping of common symptoms, a definite lack of symptom homogeneity exists and almost every patient has a unique and even fluctuating constellation of symptoms.

Chronic fatigue syndrome strikes sufferers both gradually and suddenly, though results are mixed as to which onset occurs more frequently (42; 32; 38). However, sufferers with gradual onset, because of “recruitment bias,” are traditionally underrepresented in clinical trials and, thus, represent a larger proportion of the population than previously thought (47). Further, the course may be affected by the type of onset, as those with acute onset have more frequent and severe symptoms (39), though psychiatric symptoms are generally greater among those with gradual onset (42).

The standard criteria for diagnosis are based on the 1994 Centers for Disease Control definition (17):

Prognosis and complications

The clinical course of chronic fatigue syndrome is as varied as its presentation of symptoms. The most frequently reported symptoms at the onset are sore throat, fever, muscle pain, and muscle weakness. During progression, reports of muscle pain and forgetfulness increase and reports of depression decrease. Chronic fatigue syndrome often follows a cyclic course, oscillating between periods of illness and periods of well-being (05).

Studies indicate that a complete recovery is rare. However, after 2 years, approximately 80% of patients experience some improvement; partial recovery is believed to be due to attenuation of symptom severity over time and adaptation to the altered lifestyle. These patients may experience exacerbations during periods of increased stress or illness. A significant minority of chronic fatigue syndrome sufferers experience progressive worsening of symptoms. Suicidal thoughts or feelings often occur in chronic fatigue syndrome patients with the most severe symptoms (Friedberg and Jason 1998). Patients may recover to the point of resuming normal work and activities but experience symptoms periodically. The Centers for Disease Control 4-city survey (discussed under Epidemiology) found that 50% of patients reported “recovery,” most within 5 years after the onset of symptoms (05). Further, recovery is more probable in individuals whose complaints are less severe, lesser in total number, and of a short duration (52; 33).

Biological basis

Etiology and pathogenesis

It is important to note that chronic fatigue syndrome should be differentiated between primary, secondary, and comorbid fatigue. Primary fatigue can occur on its own or be part of a disease process. For instance, fatigue in multiple sclerosis can be thought of as primary fatigue because tissue destruction of cortical and subcortical networks can lead to impairment of anatomical or function connections responsibility for energy regulation (Roelcke et al 1997; 13). In the case of multiple sclerosis, cytokine release can also mediate symptoms of fatigue (20). Secondary fatigue results from the presence of factors associated with certain disease, such as thyroid disease, mood disorders, sleep disorders, and chronic anemia. Comorbid fatigue occurs in the context of a primary disease, but is not causally related to it (35).

The cause of chronic fatigue syndrome is unknown. The development of chronic fatigue syndrome may be attributable to a single causal factor or multiple precipitating causes. Suggested etiologies include infectious (bacterial, viral), psychiatric, stress and trauma, immunologic, toxic-metabolic, and nutritional (05). Such broad etiologic categories imply lack of consensus and adequate understanding. However, chronic fatigue syndrome may represent a heterogeneous condition with different causes inciting the condition in different populations.

Because no definitive etiology has been established for chronic fatigue syndrome, pathogenetic mechanisms are unclear. Lack of illness-defining gross or histopathologic findings further obscures the pathophysiology. Because fatigue is the prominent feature of the condition, many studies focused on this complaint. Analysis of muscle biopsies was inclusive (09). Electrical studies by single-fiber EMG failed to demonstrate overt abnormalities involving the neuromuscular junction (09). Both anatomic and functional studies of the brain have been unrevealing. Detailed magnetic resonance imaging of the brain failed to distinguish patients with chronic fatigue syndrome from normal controls (45). Electroencephalograms show mild, nonspecific changes during sleep that are of dubious value (28). Studies of SPECT scans are controversial (10). Thus far, attempts to determine the physiologic basis for the symptoms, anatomic signature, and functional correlates of the disease have all been unsuccessful.

Chronic fatigue syndrome has also been linked to a variety of infectious agents, including Epstein-Barr virus, human herpes virus 6, retroviruses, cytomegalovirus, enteroviruses, stealth virus, Borna virus, and the Ross River virus (08). A proposed mechanism of the viral etiology involves Levy’s proposed “hit and run” effect, whereby an acute viral infection leads to chronic fatigue syndrome, the virus causes immune abnormalities, the virus is cleared, and the immune system remains in the activated state (24). Some suggest the presence of active, low-grade, viral infection in driving the condition. A number of inflammatory cytokines has been invoked, but to date there are no conclusive results. A study has found that leptin mediates daily cytokine fluctuations that lead to chronic fatigue syndrome (49).

The autoimmune pathogenesis of molecular mimicry is similar to that proposed for multiple sclerosis, in which the antigenic determinant recognized by the immune system closely resembles a normal cellular component. This results in cross-reaction, where the immune system is directed against a normal constituent of the cell. Evidence for autoimmunity includes reaction of chronic fatigue syndrome sera with nuclear envelope antigens, immunoprecipitation of the nuclear envelope protein lamin B1, and a high frequency of autoantibodies to insoluble cellular antigens (34). However, the presence of autoantibodies in healthy individuals warrant caution in interpretation of these studies.

An additional area of research involves chronic activation of the sympathetic nervous system. A process known as “tuning” is believed to result in increased sympathetic tone. According to this proposed mechanism, the sympathetic nervous system is activated by either a high-intensity stimulus or chronic low-intensity stimulation until it reaches a heightened state of arousal. This heightened sympathetic state leads to heightened sensitivity of the limbic system. In turn, the limbic system develops greater excitatory capacity with a decreased inhibitory state, causing the brain to become hypersensitive to stress. The hypersensitive sympathetic nervous system, therefore, causes increased neuronal firing to the point of neurotoxicity and neuronal death (Friedberg and Jason 1998). This theory is interesting, but requires development of an adequate model for testing.

Epidemiology

Initial reports indicated that chronic fatigue syndrome was a rare illness. However, methodological problems with the studies led to great underestimation and underrepresentation of the afflicted populations. The Centers for Disease Control conducted an epidemiological survey in 4 U.S. cities between 1989 and 1993 of a physician-referred population of possible chronic fatigue syndrome patients (05). This study estimated that between 4.0 and 8.7 per 100,000 people ages 18 years and older who were receiving medical care had chronic fatigue syndrome. However, these figures cannot be generalized to the U.S. population because the sites were not selected at random. More recently, the Centers for Disease Control studies found higher prevalence rates: 75 to 265 per 100,000 in San Francisco and 200 per 100,000 in Seattle (05).

Most studies of chronic fatigue syndrome indicate higher incidence rates among Caucasians and females. However, it is difficult to definitively state a higher female rate because females are more likely to seek medical treatment and as such are more visible in health care system statistics (Friedberg and Jason 1998). The aforementioned 4-city Centers for Disease Control study identified a chronic fatigue syndrome population that was 98% Caucasian and 85% female whose average age of onset was 30 years. Although chronic fatigue syndrome may occur in adolescents, the Centers for Disease Control study indicated a significantly lower frequency in the 12- to 18-year age group and did not identify chronic fatigue syndrome in children less than 12 years of age (05).

More than 80% of the population in the Centers for Disease Control study had advanced education with one third of the sample population coming from higher-income families (05). Furthermore, chronic fatigue syndrome sample populations tend to be highly educated and higher achievers. It has been hypothesized that assertive higher achievers would be less likely to accept that nothing is medically wrong on the basis of normal laboratory test results (Friedberg and Jason 1998).

The Institute of Medicine estimates that there are between 836,000 and 2.5 million Americans suffering from chronic fatigue syndrome, although they estimate that 84% to 91% of people with chronic fatigue syndrome have not been diagnosed, making measurement of prevalence difficult. Due to loss of productivity and high medical costs, there is an estimated economic burden of $17 to $24 billion annually (21).

Prevention

Contagious diseases usually occur in well-defined clusters as outbreaks or epidemics. Although fatiguing illnesses have been reported in outbreak clusters, none of the patients in the outbreaks present symptoms that fit the description of chronic fatigue syndrome. The Centers for Disease Control has yet to confirm a cluster of chronic fatigue syndrome outbreak. At this time, evidence does not indicate that chronic fatigue syndrome is a contagious disease transmitted from person to person (05).

Although there is still controversy regarding distinct predisposing factors, certain trends tend to recur in the medical histories of chronic fatigue syndrome patients. Predisposing factors for chronic fatigue syndrome include overactive lifestyle lacking adequate time for rest and reflection, long periods of stress, and history of depression. No definitive genetic links have been established.

Differential diagnosis

Chronic fatigue syndrome shares features with numerous other chronic illnesses. Table 1 lists the illnesses commonly confused with chronic fatigue syndrome (06). Some features in fibromyalgia, Gulf War syndrome, major depressive disorder, and temporomandibular disorder closely resemble those in chronic fatigue syndrome (01; 19). In addition, fibromyalgia, multiple chemical sensitivity, irritable bowel syndrome, chronic tension-type headache, and interstitial cystitis are frequent comorbid conditions.

Fibromyalgia is similar in presentation and a frequent comorbid condition. Estimates show that 20% to 80% of patients with fibromyalgia have chronic fatigue syndrome and that about 35% to 75% of patients with chronic fatigue syndrome also have fibromyalgia (22; 01). Sore throat, mild fever, or chills are the most discriminating factors between fibromyalgia and chronic fatigue syndrome. In addition, chronic fatigue syndrome and major depressive disorder were best discriminated by features of postexertional malaise, impaired memory, and unrefreshing sleep in chronic fatigue syndrome (19). The severity of symptoms also appears to distinguish chronic fatigue syndrome from some similar fatigue conditions, although symptoms can be severe in fibromyalgia and multiple chemical sensitivity (22; 19).

Table 1. Differential Diagnoses for Chronic Fatigue Syndrome

Diagnostic workup

Because there is no single test to establish the diagnosis of chronic fatigue syndrome, a diagnostic workup is performed to exclude other possible conditions. Once chronic fatigue syndrome is considered a possibility, a complete patient history and thorough examination should first be obtained to rule out contributing factors and comorbid conditions known to cause fatigue. Patient history should focus on identifying psychiatric illnesses, substance history, chronic disorders of family members that might produce fatigue, recent viral or bacterial infections, stressful lifestyle, and any other information contributing to fatigue.

The physical examination should look for presence of pallor, cardiac arrhythmia, fever or other indication of infection, weight loss, lymphadenopathy, evidence of inflammatory arthritis, occult blood loss, organomegaly, or abdominal masses, neurologic signs of impaired coordination, hypertension, edema, obesity, peripheral neuropathy, goiter, dry hair or skin, hemoptysis, or pregnancy (51).

Suggested laboratory tests include (17):

Table 2. Symptom Tests for Chronic Fatigue Syndrome

Management

Treatment of chronic fatigue syndrome is focused on the management of symptoms, particularly comorbidities such as depression, sleep, and cognitive impairment. Suggested treatment strategies include behavioral, pharmacological, immunological, nutritional, and alternative.

Behavioral modification is a popular approach. This typically involves instituting forms of graded exercise therapy or cognitive-behavioral therapy. Graded exercise therapy has shown lasting improvements in functional capacity and overall fatigue, and some evidence even suggests improvement of mood and sleep (18; 36; 30). Similarly, cognitive-behavioral therapy has reportedly led to sustained reductions in functional impairment and fatigue severity as well as pain reduction and mood improvement (07; 23). A randomized study found that graded exercise therapy and cognitive-behavioral therapy moderately improved outcomes from chronic fatigue syndrome (54). Cognitive-behavioral therapy for chronic fatigue syndrome has been studied in adolescents with positive results (50). Graded exercise therapy has also been studied in a self-administered form and was found to be effective (54). Multidisciplinary rehabilitation therapy, which is a combination of cognitive-behavioral therapy and other interventions, was found to be more effective than cognitive-behavioral therapy alone (53).

The value of pharmacological approaches is unclear. Tricyclic antidepressants may improve sleep disturbances and chronic pain (02; 44). Propranolol, a beta-blocker, may improve comorbid orthostatic intolerance and other symptoms (55). Oral NADH is said to contribute to the general relief of symptoms (16). Selegiline reportedly improved tension, anxiety, vigor, and sexual relations in selected patients (31). Antidepressants (specifically citalopram and duloxetine) did not seem to improve symptoms of fatigue (Hartz et al 2003; Arnold et al 2015). Stimulants such as methylphenidate at a dose of 10 mg twice daily increase concentration and improve overall fatigue, but their long-term benefits are still undetermined (04). Although low-dose hydrocortisone led to wellness and disability improvement in patients, its chronic use is problematic (27). A small study using modafinil did not show improvement on self-ratings of fatigue, quality of life, or mood (37).

Immunological treatments have shown some promise, but data are often inconclusive and limited. Rintatolimod, a double-stranded RNA immunomodulatory agent that is attributed to be an agonist of TLR-3 (although dsRNA analogues typically bind TLR-7 and 8), is said to improve both cognitive and physical deficits (48; Strayer et al 2012). A panel at the U.S. Food and Drug Administration voted 8 to 5 against its use. Immunoglobulin infusions reportedly improve general functioning in some patients (25; 41). Improvement after staphylococcus toxoid injections has been reported, but further studies are needed (56). An IL-1 inhibitor did not show any benefit in improving symptoms of chronic fatigue syndrome as it did not differ from placebo (40).

Fatty acid, acetylcarnitine and propionylcarnitine, and magnesium supplementation studies are inconclusive. In a trial of 434 patients, galantamine did not show any benefit (03).

A trial examined whether rituximab, an anti-CD20 monoclonal antibody, would lead to improvement in measurements of fatigue (Fluge et al 2011). The primary endpoint, which was defined as effect on self-reported fatigue score 3 months after intervention, was negative. However, using a self-reported fatigue scale, there was major or moderate overall response in 11 out of 15 patients (67%) in the rituximab group, with only 2 out of 15 patients (13%) in the placebo group.

Alternative therapeutic approaches such as acupuncture, massage therapy, herbal therapy, Chinese qigong therapy, and thermal therapy are advocated by certain groups, but in the absence of a carefully designed trial, are difficult to assess (12; 26; 46).

Special considerations

Pregnancy

Frequency of spontaneous abortion was nearly 4-fold in those whose onset occurred after pregnancy (43).