Section 4: Chronic Fatigue Syndrome

DEFINITION

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, 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 464e-1).

EPIDEMIOLOGY

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. The mean age of onset is between 29 and 35 years. Many patients probably go undiagnosed and/or do not seek help.

ETIOLOGY

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 464e-2).

Predisposing Factors

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 no causative genes have been identified.

Precipitating Factors

Physical or psychological stress may elicit the onset of CFS. Most patients report an infection (usually 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. One study identified a murine leukemia virus–related retrovirus (XMRV); however, several subsequent studies have established this virus as a laboratory artifact. 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.

Perpetuating Factors

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 illness 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.

PATHOPHYSIOLOGY

The pathophysiology of CFS is unclear. Neuroimaging studies have found that CFS is associated with reduced gray matter volume, which in turn is associated with a decline in physical activity; these changes have been partially reversed following cognitive behavioral therapy (CBT). In addition, 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 appears 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 CBT. Discrepancies in perceived and actual cognitive performance are consistent findings in patients with CFS.

DIAGNOSIS

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. 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 specific abnormalities have been identified on MRI or CT scans. The decrease in gray matter volume observed at a population level by MRI is not useful for diagnosis in the individual patient. 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 issues 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.

INITIAL MANAGEMENT

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 fulfils all criteria (Table 464e-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. 464e-1).

The patient should be informed of the current understanding of precipitating and perpetuating factors and effective treatments and should be offered 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

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.