Chronic fatigue syndrome (CFS) is a disorder characterized by persistent and unexplained fatigue resulting in severe impairment in daily functioning. Besides intense fatigue, most patients with CFS report concomitant symptoms such as pain, cognitive dysfunction, and unrefreshing sleep. Additional symptoms can include headache, sore throat, tender lymph nodes, muscle aches, joint aches, post-exertional malaise, feverishness, difficulty sleeping, psychiatric problems, allergies, and abdominal cramps. Criteria for the diagnosis of CFS have been developed by the U.S. Centers for Disease Control and Prevention (Table 442-1). The Institute of Medicine (IOM; now the National Academy of Medicine) has recently changed the diagnostic criteria and proposed the name systemic exercise intolerance disease (SEID). To date, however, no studies have been reported to demonstrate the usefulness of this change.
TABLE 442-1Diagnostic Criteria for Chronic Fatigue Syndrome ||Download (.pdf) TABLE 442-1 Diagnostic Criteria for Chronic Fatigue Syndrome
|Characteristic Persistent or Relapsing Unexplained Chronic Fatigue |
|Fatigue lasts for at least 6 months. |
|Fatigue is of new or definite onset. |
|Fatigue is not the result of an organic disease or of continuing exertion. |
|Fatigue is not alleviated by rest. |
|Fatigue results in a substantial reduction in previous occupational, educational, social, and personal activities. |
|Four or more of the following symptoms are concurrently present for 6 months: impaired memory or concentration, sore throat, tender cervical or axillary lymph nodes, muscle pain, pain in several joints, new headaches, unrefreshing sleep, or malaise after exertion. |
|Exclusion Criteria |
|Medical condition explaining fatigue |
|Major depressive disorder (psychotic features) or bipolar disorder |
|Schizophrenia, dementia, or delusional disorder |
|Anorexia nervosa, bulimia nervosa |
|Alcohol or substance abuse |
|Severe obesity (body mass index >40) |
CFS is seen worldwide, with adult prevalence rates varying between 0.2 and 0.4%. In the United States, the prevalence is higher among women (~75% of cases), members of minority groups (African and Native Americans), and individuals with lower levels of education and occupational status. CFS has been reported to be associated with an increase in mortality from suicide. The mean age of onset is between 29 and 35 years. Many patients probably go undiagnosed and/or do not seek help.
There are numerous hypotheses about the etiology of CFS; there is no definitively identified cause. Distinguishing between predisposing, precipitating, and perpetuating factors in CFS helps to provide a framework for understanding this complex condition (Table 442-2).
TABLE 442-2Predisposing, Precipitating, and Perpetuating Factors in Chronic Fatigue Syndrome ||Download (.pdf) TABLE 442-2 Predisposing, Precipitating, and Perpetuating Factors in Chronic Fatigue Syndrome
|Predisposing Factors |
|Childhood trauma (sexual, physical, emotional abuse; emotional and physical neglect) |
|Physical inactivity during childhood |
|Premorbid psychiatric illness or psychopathology |
|Premorbid hyperactivity |
|Precipitating Factors |
|Somatic events: infection (e.g., mononucleosis, Q fever, Lyme disease), surgery, pregnancy |
|Psychosocial stress, life events |
|Perpetuating Factors |
|Non-acknowledgment by physician |
|Negative self-efficacy |
|Strong physical attributions |
|Strong focus on bodily symptoms |
|Fear of fatigue |
|Lack of social support |
|Low physical activity pattern |
Physical inactivity and trauma in childhood tend to increase the risk of CFS in adults. Neuroendocrine dysfunction may be associated with childhood trauma, reflecting a biological correlate of vulnerability. Psychiatric illness and physical hyperactivity in adulthood raise the risk of CFS in later life. Twin studies suggest a familial predisposition to CFS, but research into causative genes has yielded variable results. In a recent systematic review, a number of single nucleotide polymorphisms encoding for TNFalpha, IL-1beta, IL-6 and IL-4 were found to be associated with increased fatigue in CFS, cancer-related fatigue, and other disease-related fatigue states.
Physical or psychological stress may elicit the onset of CFS. A substantial number of patients report an infection (often a flulike illness or infectious mononucleosis) as the trigger of their fatigue. Relatively high percentages of CFS cases follow Q fever and Lyme disease. However, no differences in Epstein-Barr virus load and immunologic reactivity were found between individuals who developed CFS and those who did not. While antecedent infections are associated with CFS, a direct microbial causality is unproven and unlikely. Patients also often report other precipitating somatic events such as serious injury, surgery, pregnancy, or childbirth. Serious life events, such as the loss of a loved one or a job, military combat, and other stressful situations, may also precipitate CFS. One-third of all patients cannot recall a trigger.
Once CFS has developed, numerous factors may impede recovery. Physicians may contribute to chronicity by ordering unnecessary diagnostic procedures, by persistently suggesting psychological causes, and by not acknowledging CFS as a diagnosis.
A patient’s focus on symptoms and avoidance of activities may perpetuate symptoms. A firm belief in a physical cause, a strong focus on bodily sensations, and a poor sense of control over symptoms may also prolong or exacerbate the fatigue and functional impairment. In most patients, inactivity is caused by negative illness perceptions rather than by poor physical fitness. Solicitous behavior of others may reinforce a patient’s illness-related perceptions and behavior. A lack of social support is another known perpetuating factor.
The pathophysiology of CFS is unclear. Neuroimaging studies have suggested that CFS is associated with reduced gray matter volume, but recent studies seem to indicate that pain rather than fatigue is associated with these changes. Functional MRI data have suggested that abnormal patterns of activation correlate with self-reported problems with information processing. Neurophysiologic studies have shown altered CNS activation patterns during muscle contraction.
Evidence for immunologic dysfunction is inconsistent. Modest elevations in titers of antinuclear antibodies, reductions in immunoglobulin subclasses, deficiencies in mitogen-driven lymphocyte proliferation, reductions in natural killer cell activity, disturbances in cytokine production, and shifts in lymphocyte subsets have been described. None of these immune findings has been firmly established and none of these changes appear in most patients, nor does any correlate with the severity of CFS. In theory, symptoms of CFS could result from excessive production of a cytokine, such as interleukin 1, that induces asthenia and other flulike symptoms; however, compelling data in support of this hypothesis are lacking. There is some evidence that CFS patients have mild hypocortisolism, the degree of which is associated with a poorer response to cognitive-behavioral therapy (CBT). Discrepancies in perceived and actual cognitive performance are consistent findings in patients with CFS.
In addition to a thorough history, a systematic physical examination is warranted to exclude disorders causing fatigue (e.g., endocrine disorders, neoplasms, heart failure). The heart rate of CFS patients is often slightly above normal, but postural hypotension, which has been included in the diagnostic criteria put forward by the IOM (see above), is not more common in CFS patients than in controls. Laboratory tests serve primarily to exclude other diagnoses; no test can diagnose CFS. The following laboratory screen usually suffices: complete blood count; erythrocyte sedimentation rate; C-reactive protein; serum creatinine, electrolytes, calcium, and iron; blood glucose; creatine kinase; liver function tests; thyroid-stimulating hormone; anti-gliadin antibodies; and urinalysis. Serology for viral or bacterial infections usually is not helpful. No diagnostic abnormalities have been identified on MRI or CT scans. Extensive, unfocused, and expensive testing in a search for the “hidden” cause of the fatigue is not productive. CFS is a constellation of symptoms with no pathognomonic features and remains a diagnosis of exclusion.
Bipolar disorders, schizophrenia, and substance abuse exclude a diagnosis of CFS, as do eating disorders, unless these health problems have been resolved ≥5 years before symptom onset. In addition, CFS is excluded if the chronic fatigue developed immediately after a depressive episode. Depression developing in the course of the fatigue, however, does not preclude CFS. Concurrent psychiatric disorders, especially anxiety and mood disorders, are present in 30–60% of cases.
In cases of suspected CFS, the clinician should acknowledge the impact of the patient’s symptoms on daily functioning. Disbelief or denial can provoke an exacerbation of genuine symptoms, which in turn strengthens the clinician’s disbelief, leading to an unfortunate cycle of miscommunication. The possibility of CFS should be considered if a patient fulfills all criteria (Table 442-1) and if other diagnoses have been excluded.
The patient should be asked to describe the symptoms (fatigue and accompanying symptoms) and their duration as well as their consequences (reduction in daily activities). To assess symptom severity and the extent of daily-life impairment, the patient should describe a typical day, from waking to retiring, and, for comparison, an average day prior to symptom onset. Next, potential fatigue-precipitating factors are sought. The severity of fatigue is commonly difficult to assess quantitatively; a brief questionnaire is often helpful (Fig. 442-1).
Shortened fatigue questionnaire.
The patient should be informed of the current understanding of precipitating and perpetuating factors and effective treatments and provided general advice about disease management. If CBT for CFS is not available as an initial option (see below) and depression and anxiety are present, these symptoms should be treated. For patients with headache, diffuse pain, and feverishness, nonsteroidal anti-inflammatory drugs may be helpful. Even modest improvements in symptoms can make an important difference in the patient’s degree of self-sufficiency and ability to appreciate life’s pleasures.
Controlled therapeutic trials have established that acyclovir, fludrocortisone, galantamine, modafinil, and IV immunoglobulin, among other agents, offer no significant benefit in CFS. Countless anecdotes circulate regarding other traditional and nontraditional therapies. It is important to guide patients away from those therapeutic modalities that are toxic, expensive, or unreasonable.
The patient should be encouraged to maintain regular sleep patterns, to remain as active as possible, and to gradually return to previous levels of exercise and other activity (work).
TREATMENT Chronic Fatigue Syndrome
CBT and graded exercise therapy (GET) have been found to be the only beneficial interventions in CFS. Some patient groups argue against these approaches because of the implication that CFS is a purely mental disorder. CBT is a psychotherapeutic approach directed at changing unhealthy disease-perpetuating patterns of thoughts and behaviors. It includes educating the patient about the etiologic model, setting goals, restoring fixed bedtimes and wake-up times, challenging and changing fatigue- and activity-related concerns, reducing a focus on symptoms, spreading activities evenly throughout the day, gradually increasing physical activity, planning a return to work, and resuming other activities. The intervention, typically consisting of 12–14 sessions over 6 months performed by an experienced cognitive behavior therapist, helps CFS patients gain control over their symptoms.
GET targets deconditioning and exercise intolerance and usually involves a home exercise program that continues for 3–5 months. Walking or cycling is systematically increased, with set goals for maximal heart rates. Evidence that deconditioning is the basis for symptoms in CFS is lacking, however. CBT and GET appear to improve fatigue primarily by changing the patient’s perception of the fatigue and also by reducing the focus on symptoms.
CBT and GET seem equally effective, however not all patients benefit from these interventions. Predictors of poor outcome are insufficient motivation for the treatment, medical (including psychiatric) comorbidities, current disability claims, and severe pain. CBT offered in an early stage of the illness reduces the burden of CFS for the patient as well as for society in terms of decreased medical and disability-related costs. PROGNOSIS
Full recovery from untreated CFS is rare: the median annual recovery rate is 5% (range, 0–31%), and the median improvement rate is 39% (range, 8–63%). Patients with an underlying psychiatric disorder and those who continue to attribute their symptoms to an undiagnosed medical condition have poorer outcomes.
et al: Chronic fatigue syndrome and circulating cytokines: A systematic review. Brain Behav Immun 50:186, 2015.
et al: Cognitive behavioral therapy and graded exercise for chronic fatigue syndrome: A meta-analysis. Clin Psychol Sci Prac 18:311, 2011.
Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: Redefining an illness. National Academies Press, Washington, DC, 2015.
et al: Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev 12:CD003200, 2016.