Harrison's Neurology in Clinical Medicine, 3rd Edition


Gijs Bleijenberg Image Jos W.M. van der Meer


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 52-1).

TABLE 52-1




CFS is seen worldwide, with adult prevalence rates varying between 0.2 and 0.4%. In the United States, the prevalence is higher in women, members of minority groups (African and Native Americans), and individuals with lower levels of education and occupational status. Approximately 75% of all CFS patients are women. The mean age of onset is between 29 and 35 years. It is probable that many patients go undiagnosed and/or do not seek help.


There are numerous hypotheses about the etiology of CFS; there is no definitively indentified cause. Distinguishing between predisposing, precipitating, and perpetuating factors in CFS helps to provide a framework for understanding this complex condition (Table 52-2).

TABLE 52-2



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 follow Q fever and Lyme disease. However, no differences were found in Epstein-Barr virus load and immunologic reactivity in individuals who developed CFS and those who did not. While antecedent infections are associated with CFS, a direct microbial causality is unproven and unlikely. A recent study identified a murine leukemia virus-related retrovirus (XMRV); however, several subsequent studies have failed to confirm this result. 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. A 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.


The pathophysiology of CFS is unclear. Neuroimaging studies have reported that CFS is associated with reduced gray matter volume, associated with a decline in physical activity; these changes were 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 appear in most patients, nor do 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 a consistent finding 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, etc.). The heart rate of CFS patients is often slightly above normal. Laboratory tests primarily serve to exclude other diagnoses; there is no test that can diagnose CFS. The following laboratory screen usually suffices: complete blood count; ESR, CRP; serum creatinine, electrolytes, calcium and iron; blood glucose; creatine kinase; liver function tests; TSH; anti-gliadin antibodies; urinalysis. Serology for viral or bacterial infections is usually not helpful. No specific abnormalities have been identified on MRI or CT scans. CFS is a constellation of symptoms without any 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 have been resolved 5 years or longer before symptom onset. Also, 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. Co-occurring psychiatric disorder, especially anxiety and mood disorders, is seen in 30–60% of all 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 fulfils all criteria (Table 52-1) 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 the 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 to contrast this with an average day prior to symptom onset. Next, potential fatigue-precipitating factors are sought. The severity of fatigue is difficult to assess quantitatively; a brief questionnaire is often helpful (Fig. 52-1).



Shortened fatigue questionnaire (SFQ).

The patient should be informed of the current understanding of precipitating and perpetuating factors and effective treatments, and be offered general advice about disease management. If CBT for CFS is not available as an initial treatment 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 exercise and activity (work) levels.

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 condition-related cognitions and behaviors. CBT for CFS aims at changing a patient’s perpetuating factors by exploiting various techniques and components. It includes educating the patient about the etiologic model, setting goals, restoring fixed bedtime and wake-up time, challenging and changing fatigue- and activity-related cognitions, reducing symptom focusing, spreading activities evenly throughout the day, gradually increasing physical activity, planning a return to work, and resuming other activities. The intervention, which typically consists of 12–14 sessions spread over 6 months, helps CFS patients gain control over their symptoms.

GET is based on the model of 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 target heart rates. Evidence that deconditioning is the basis for symptoms in CFS is lacking, however. The primary component of CBT and GET that results in a reduction in fatigue is the change in the patient’s perception of fatigue and focus on symptoms.

CBT is generally the more complex treatment, which might explain why CBT studies tend to yield better improvement rates than GET trials.

Not all patients benefit from CBT or GET. Predictors of poor outcome are somatic comorbidity, 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 society in terms of decreased medical and disability-related costs.


Full recovery from untreated CFS is rare: the median annual recovery rate is 5% (range 0–31%) and the improvement rate 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.