Fatigue is one of the most common symptoms in clinical medicine. It is a prominent manifestation of a number of systemic, neurologic, and psychiatric syndromes, although a precise cause will not be identified in a substantial minority of patients. Fatigue refers to an inherently subjective human experience of physical and mental weariness, sluggishness, and exhaustion. In the context of clinical medicine, fatigue is most typically and practically defined as difficulty initiating or maintaining voluntary mental or physical activity. Nearly everyone who has ever been ill with a self-limited infection has experienced this near-universal symptomatology, and fatigue is usually brought to medical attention only when it is either of unclear cause or the severity is out of proportion with what would be expected for the associated trigger. Fatigue should be distinguished from muscle weakness, a reduction of neuromuscular power (Chap. 14); most patients complaining of fatigue are not truly weak when direct muscle power is tested. By definition, fatigue is also distinct from somnolence and dyspnea on exertion, although patients may use the word fatigue to describe those two symptoms. The task facing clinicians when a patient presents with fatigue is to identify an underlying cause if one exists and to develop a therapeutic alliance, the goal of which is to spare patients expensive and fruitless diagnostic workups and steer them toward effective therapy.

Variability in the definitions of fatigue and the survey instruments used in different studies makes it difficult to arrive at precise figures about the global burden of fatigue. The point prevalence of fatigue was 6.7% and the lifetime prevalence was 25% in a large National Institute of Mental Health survey of the U.S. general population. In primary care clinics in Europe and the United States, between 10 and 25% of patients surveyed endorsed symptoms of prolonged (present for >1 month) or chronic (present for >6 months) fatigue, but fatigue was the primary reason for seeking medical attention in only a minority of patients. In a community survey of women in India, 12% reported chronic fatigue. By contrast, the prevalence of chronic fatigue syndrome, as defined by the U.S. Centers for Disease Control and Prevention, is low (Chap. 59).

Psychiatric disease

Fatigue is a common somatic manifestation of many major psychiatric syndromes, including depression, anxiety, and somatoform disorders. Psychiatric symptoms are reported in more than three-quarters of patients with unexplained chronic fatigue. Even in patients with systemic or neurologic syndromes in which fatigue is independently recognized as a manifestation of disease, comorbid psychiatric symptoms or disease may still be an important source of interaction.

Neurologic disease

Patients complaining of fatigue often say they feel weak, but upon careful examination, objective muscle weakness is rarely discernible. If found, muscle weakness must then be localized to the central nervous system, peripheral nervous system, neuromuscular junction, or muscle and the appropriate follow-up studies obtained (Chap. 14). Fatigability of muscle power is a cardinal manifestation of some neuromuscular disorders such as myasthenia gravis and can be distinguished from fatigue by finding clinically apparent diminution of the amount of force that a muscle generates upon repeated contraction (Chap. 55). Fatigue is one of the most common and bothersome symptoms reported in multiple sclerosis (MS) (Chap. 45), affecting nearly 90% of patients; fatigue in MS can persist between MS attacks and does not necessarily correlate with magnetic resonance imaging (MRI) disease activity. Fatigue is also increasingly identified as a troublesome feature of many other neurodegenerative diseases, including Parkinson’s disease, central dysautonomias, and amyotrophic lateral sclerosis. Poststroke fatigue is a well-described but poorly understood entity with a widely varying prevalence. Episodic fatigue can be a premonitory symptom of migraine. Fatigue is also a frequent result of traumatic brain injury, often occurring in association with depression and sleep disorders.

Sleep disorders

Obstructive sleep apnea is an important cause of excessive daytime sleepiness in association with fatigue and should be investigated using overnight polysomnography, particularly in those with prominent snoring, obesity, or other predictors of obstructive sleep apnea. Whether the cumulative sleep deprivation that is common in modern society contributes to clinically apparent fatigue is not known (Chap. 24).

Endocrine disorders

Fatigue, sometimes in association with true muscle weakness, can be a heralding symptom of hypothyroidism, particularly in the context of hair loss, dry skin, cold intolerance, constipation, and weight gain. Fatigue in association with heat intolerance, sweating, and palpitations is typical of hyperthyroidism. Adrenal insufficiency can also manifest with unexplained fatigue as a primary or prominent symptom, often in association with anorexia, weight loss, nausea, myalgias, and arthralgias; hyponatremia and hyperkalemia may be present at time of diagnosis. Mild hypercalcemia can cause fatigue, which may be relatively vague, whereas severe hypercalcemia can lead to lethargy, stupor, and coma. Both hypoglycemia and hyperglycemia can cause lethargy, often in association with confusion; chronic diabetes, particularly type 1 diabetes, is also associated with fatigue independent of glucose levels. Fatigue may also accompany Cushing’s disease, hypoaldosteronism, and hypogonadism.