Definition

Chronic fatigue syndrome (CFS) is a debilitating condition of unknown nature and cause, but most medical authorities now accept its existence. CFS is characterized by severe, disabling, medically unexplained fatigue for more than 6 months and prominently features subjective impairments in concentration, short-term memory, and sleep as well as musculoskeletal pain [1]. Sufferers experience significant disability and distress, which may be further exacerbated by a lack of understanding from others, including health professionals. CFS affects both adults and children.

Epidemiologic research in Western countries has demonstrated that among adults, between 230 and 500 of every 100,000 persons are affected with CFS [2–4]. Women have CFS more commonly [5], as do minority groups and people with lower educational status and educational attainment [2].

The causes of CFS remain uncertain. CFS may start either gradually or suddenly. In the latter case, it is often triggered by an influenza-like viral or similar illness. Some progress in the understanding of the disease has been made when causes were divided into predisposing, triggering or precipitating, and perpetuating factors [6,7]. Personality (neuroticism, introversion) and lifestyle factors, inactivity in childhood and inactivity after infectious mononucleosis, and genetic factors are presumed to influence vulnerability in CFS. Certain infectious illnesses (e.g., Epstein-Barr virus infection, Q fever, and Lyme disease), precipitating somatic events (e.g., serious injuries), and psychological distress (e.g., serious life events) may precipitate the disorder. The perceptions, illness attributions, and beliefs of patients may encourage avoidant coping and perpetuate the illness.

Among various pathophysiologic hypotheses tested, some evidence has emerged supporting subtle hypoactivity in the hypothalamic-pituitary-adrenal axis with lower than normal cortisol response to increased corticotropin levels [8] and a hyperserotonergic state or upregulated serotonin receptors in CFS [9,10]. Whether these alterations are a cause or a consequence of CFS, however, remains unclear. Dysfunction in the immune system in CFS is inconsistently evidenced by findings of abnormal cytokine production, mainly concentrating on proinflammatory ones that are known to be involved in the regulation of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, such as tumor necrosis factor, interleukin-1, and interleukin-6 [11]. On the tissue level, cytokines such as interleukin-6 are involved in the stress response and represent crucial inducers of sickness behavior [12], which is characterized by avoidance behavior, apathy, sleepiness, impaired memory and concentration, anorexia, mild fever, and increased sensitivity to pain. No convincing evidence exists to support CFS as a continuing viral infection [11]. Increasing evidence suggests that in a large subgroup of CFS patients, central sensitization with widespread hyperalgesia, delayed diffuse noxious inhibitory control, and dysfunction of endogenous inhibition during exercise seems to corroborate several psychological influences on the illness [13]. Functional magnetic resonance imaging studies in patients with CFS revealed findings indicative of increased neuronal resource allocation [14] or dysfunctional motor planning [15], which seems to be consistent with cognitive impairment in these patients.

Symptoms

Patients with CFS typically present with a variety of symptoms that may widely overlap with symptoms of functional somatic syndromes, including the irritable bowel syndrome, fibromyalgia, multiple chemical sensitivity, chronic pelvic pain, temporomandibular joint dysfunction, and Gulf War illness [11].

Patients experience profound, overwhelming exhaustion, both mentally and physically, which is worsened by exertion and is not completely relieved by rest [16]. Fatigue is highly subjective, multidimensional, and variable in nature, and it does not necessarily need to be the major and most debilitating symptom in this condition [1]. Patients may express their complaints of fatigue in different ways. Patients’ expectations and causal attribution of symptoms to somatic factors, hidden agenda involving insurance issues, and invalidity of benefit claims have been related to an increase in symptoms and may contribute to a diversity of symptoms reported [7].

In addition to fatigue, patients with CFS usually complain about a wide variety of multisystem symptoms that are nonspecific and variable in both nature and severity over time. These may be just as prominent as fatigue and are best summarized in different categories [16,17].

• Complaints of cognitive dysfunction. CFS patients may experience forgetfulness, confusion, difficulties in thinking, and “mental fatigue” or “brain fog.”

• Postexertional malaise. Patients report a period of deep fatigue and exhaustion that lasts for more than 24 hours after physical exertion.

• Complaints of pain. These include headaches of a new type, pattern, or severity; muscle pain; and multijoint pain. Patients may further report pain in bones, eyes, and testicles; abdominal and chest pain; chills; and painful skin sensitivity.

• Unrefreshing sleep and rest is a hallmark of CFS, and insomnia is also common. Patients report more difficulty in falling asleep, more interrupted sleep, and more daytime napping. It is extremely difficult for many patients to maintain a sleep schedule. Patients report that exercise, unlike in healthy persons, worsens the insomnia and unrefreshing sleep symptoms alike.

• Psychological complaints of emotional lability, anxiety, depressive mood, irritability, and sometimes a curious emotional “flattening” most likely due to exhaustion may be reported by CFS patients. CFS patients with preexisting psychiatric symptoms may report that these worsen with the onset of CFS. Treatment of psychiatric symptoms alone does not relieve the physical symptoms of CFS, indicating that the disease is not only psychological in nature.

• Other frequently reported complaints refer to general hypersensitivity and poor temperature control; these include low-grade fevers, photophobia, vertigo, nausea, allergies, hot flashes, and rashes [18,19].

Physical Examination

The physical examination is directed toward determination of whether symptoms are caused by any other disease or illness. The findings of the general medical and neurologic examinations should be normal. There may be low-grade fever with temperatures between 37.5° C and 38.5° C orally, nonexudative pharyngitis, and tender cervical or axillary lymph nodes up to 2 cm in diameter. A mild hypotension, elicited mainly with tilt-table testing and reversed by mineralocorticoids, may be observed. In some patients, orthostatic hypotension with wide swings in blood pressure resulting in syncope as well as intermittent hypertension may be found [20]. Complaints of paresthesias usually prove to be odd on sensory testing, particularly numbness in the bones or muscles or fluctuating patches of numbness or paresthesias on the chest, face, or nose. A few patients report blurred or “close to” double vision. In neither case are there physical findings to corroborate the sensory experiences [20]. Unsteadiness on standing with closed eyes may be found.

A thorough mental status examination is performed to rule out any exclusionary psychiatric disorders. The psychological examination may reveal abnormalities in mood, intellectual function, memory, concentration, and personality. Particular attention should be paid to anxiety, self-destructive thoughts, and observable signs such as psychomotor retardation [1].

The musculoskeletal examination findings should be normal. In CFS patients with arthralgia and myalgia, joint swelling and inflammation and other superimposed pain generators, such as bursitis, tendinitis, and radiculopathy, have to be ruled out. Palpatory examination of muscles may reveal tender muscles, tender points that are not numerous enough to be classified as fibromyalgia, and individual trigger points.

Functional Limitations

Disablement varies widely among patients with CFS. Whereas some are able to lead a relatively normal life, others are totally bed bound and unable to care for themselves. In a rehabilitative assessment, body functions that represent the patient’s core subjective symptoms may reveal the most pronounced impairment; these are energy and drive functions, sensation of pain, sleep functions, attention function, emotional functions, memory functions, and exercise tolerance functions. Both muscle and cardiopulmonary function as demonstrated by cardiopulmonary stress testing may be reduced in these patients. Avoidance behavior as a consequence of patients’ experiencing worsening of symptoms after previously well-tolerated levels of exercise and kinesiophobia—a specific kind of fear-avoidance behavior that is defined as an excessive, irrational, and debilitating fear of physical movement and activity resulting from a feeling of vulnerability to painful injury or reinjury—may increase sedentariness in CFS patients. However, kinesiophobia was not correlated with reduced exercise capacity by bicycle ergometer exercise stress testing [21].

CFS patients may be able to begin but not to complete mental or physical activities that were previously easily accomplished. Thus, tasks that predominantly challenge the cognitive performance, like focusing attention, solving problems, handling stress, making decisions, undertaking multiple tasks, or driving a car, may limit patients in carrying out their daily routine, especially at the workplace. Tasks that require predominantly physical performance, like walking or household tasks, may limit the patient’s activities of daily life. Many patients have to modify or give up physical hobbies and exercise and find themselves unable to work full-time or at all [17]. Categories related to intimate relationships, family relationships, communication, and complex interpersonal relationships may be altered in CFS patients, thereby restricting them from participation in social and work life.

Cognitive avoidance coping as a major illness-perpetuating factor was found negatively related to social functioning [22], and a strong association seems to exist between kinesiophobia and self-reported activity limitations and participation restrictions in CFS patients [21]. In addition to environmental factors related to the immediate family and friends, health professionals may reinforce patients’ symptom severity and illness behavior and facilitate further impaired functioning in these patients. Personal beliefs, practices, ideologies, spirituality, laws, and societal norms may also facilitate or hinder functioning in CFS patients. A considerable number of patients with CFS in many countries are receiving disability benefits or private insurance or have made claims and been denied [23].

Diagnostic Studies

There are no accepted diagnostic tests for CFS. Diagnosis of CFS is primarily based on the patient’s symptoms that fit scientific case definitions of CFS, which aim to effectively distinguish CFS from other types of unexplained fatigue. Among numerous scientific case definitions available, the U.S. Centers for Disease Control and Prevention criteria are the most widely supported [1]. This case definition characterizes CFS by a grouping of nonspecific symptoms and a diagnosis of exclusion (Table 125.1). To receive a diagnosis of CFS, fatigue must have persisted or recurred during 6 or more consecutive months. Concomitant symptoms must have persisted or recurred during 6 or more consecutive months of illness and cannot have predated the fatigue [16]. Clinicians may have difficulties in diagnosis of CFS, especially by not acknowledging the diagnosis of fatigue when its onset is gradual or by the diversity of patients’ fatigue reports. Instruments developed to assess fatigue, such as the Checklist Individual Strength, the Chalder Fatigue Scale, and the Krupp Fatigue Severity Scale, are widely used in research studies and may assist physicians with objectivation of fatigue and establishment of the medical diagnosis.