In this chapter, we consider the clinically related phenomena of lassitude, fatigue, nervousness, irritability, anxiety, and depression. These complaints form the core of a group of “symptom-based” disorders that are a large part of medical practice. Although more abstruse than paralysis, sensory loss, seizures, or aphasia, they are no less important, if for no other reason than their frequency. In an audit of one neurologic practice, anxiety and depressive reactions were the main diagnosis in 20 percent of patients, second only to the symptom of headache (Digon et al). Similarly, in two primary care clinics in Boston and Houston, fatigue was the prominent complaint in 21 and 24 percent of patients, respectively. Some of these symptoms represent only slight aberrations of function or a heightening or exaggeration of normal reactions to environmental stress or to medical and neurologic diseases; others are integral features of the diseases themselves; and still others represent disturbances of neuropsychiatric function that are components of the diseases described in Chaps. 51, 52, and 53 on psychiatry.

Of the symptoms considered in this chapter, lassitude and fatigue are the most frequent, and the most vague. Fatigue refers to the universally familiar state of weariness or exhaustion resulting from physical or mental exertion. Lassitude has much the same meaning, although it connotes more of an inability or disinclination to be active, physically or mentally. More than half of all patients entering a general hospital register a complaint of fatigability or admit to it when questioned. During World War I, fatigue was such a prominent symptom in combat personnel as to be given a separate place in medical nosology, namely combat fatigue, a term that came to be applied to practically all acute psychiatric disorders occurring on the battlefield. In subsequent wars, it has become a key element of the posttraumatic stress disorders related to exposure to highly stressful circumstances. The common clinical antecedents and accompaniments of fatigue, its significance, and its physiologic and psychologic bases will be better understood if we first consider the effects of fatigue on the normal individual.

Effects of Fatigue on the Normal Person

Fatigue has three basic meanings: (1) biochemical and physiologic changes in muscles and a reduced capacity to generate force manifest as weakness, or asthenia; (2) a disorder in behavior, taking the form of a reduced output of work (work decrement) or a lack of endurance; and (3) a subjective feeling of tiredness and discomfort.

The decreased productivity and capacity for work, which is a direct consequence of fatigue, has been investigated by industrial psychologists. Their findings clearly demonstrate the importance of motivational factors on work output, whether the effort is of physical or mental type. Quite striking are individual constitutional differences in energy, which vary greatly, just as do differences in temperament. What should be emphasized is that in the majority of persons complaining of fatigue, one does not find true muscle weakness. This may be difficult to prove, for many such individuals are disinclined to exert full effort in tests of peak power of muscle contraction or in endurance of muscular activity.

The Clinical Significance of Fatigue

Patients experiencing lassitude and fatigue have a more or less characteristic way of expressing their symptoms. They say that they are “wiped, or burned out,” “tired all the time,” “weary,” “exhausted,” or “pooped out,” or that they have “no pep,” “no ambition,” or “no interest.” They manifest their condition by showing an indifference to the tasks at hand, by emphasizing how hard they are working, and how stressed they are by circumstances; they are inclined to sit around or lie down or to occupy themselves with trivial tasks. On closer analysis, one observes and hears that many such patients have difficulty in initiating activity and also in sustaining it; i.e., their endurance is diminished. This condition, of course, is the familiar aftermath of sleeplessness or prolonged mental or physical effort, and, under such circumstances, it is accepted as a normal physiologic reaction. When, however, similar symptoms appear without relation to such antecedents, they should be suspected of being the manifestations of disease.

The physician’s task is initially to determine whether the patient is merely suffering from the common physical and mental effects of overwork. Overworked, overwrought people are observable everywhere in our society. In addition to fatigue, such persons frequently show irritability, restlessness, sleeplessness, and anxiety, sometimes to the point of panic attacks and a variety of somatic symptoms, particularly abdominal, thoracic, and cranial discomforts. Formerly, society accepted this state in responsible individuals and prescribed the obvious cure, a vacation. Even Charcot made time for regular “cures” during the year, in which he retired to a spa without family, colleagues, or the drain of work. Nowadays, the need to contain this type of stress, to which some individuals are more prone than others, has spawned an industry of meditation, yoga, and similar activities. Individuals with hobbies, nonwork interests, and athletic pursuits seem to be less subject to this problem. A common error in diagnosis, however, is to ascribe fatigue to overwork when actually it is a manifestation of anxiety or depression, as described below.

Fatigue as a Symptom of Psychiatric Illness

The majority of patients who seek medical help for unexplained chronic fatigue and lassitude are found to have some type of psychiatric illness. Formerly this state was called “neurasthenia,” a term introduced by Beard, but because lassitude and fatigue rarely exist as isolated phenomena, the current practice is to label such cases according to the total clinical picture. The usual associated symptoms are anxiety, irritability, depression, insomnia, headaches, dizziness, difficulty in concentrating, reduced sexual drive, and loss (or sometimes increase) of appetite. In one series, 85 percent of persons admitted to a general hospital and seen in consultation by a psychiatrist for the chief complaint of chronic fatigue were diagnosed, finally, as having anxious depression or an anxiety state. In a subsequent study, Wessely and Powell found similarly that 72 percent of patients who presented to a neurologic center with unexplained chronic fatigue proved to have a psychiatric disorder, most often a depressive illness.

Several features are common to the psychiatric group with fatigue. Tests of peak muscle power on command, with the patient exerting full effort, reveal no weakness. The sense of fatigue may be worse in the morning. There is an inclination to lie down and rest, but sleep does not follow. The fatigue is worsened by mild exertion and relates more to some activities than to others. Inquiry may disclose that the symptom was first experienced in temporal relation to a grief reaction, a surgical procedure, physical trauma such as an automobile accident, or a medical illness such as myocardial infarction. The feeling of fatigue interferes with both mental and physical activities; the patient is easily worried, is “full of complaints,” and finds it difficult to concentrate in attempting to solve a problem or to read a book, or in carrying on a complicated conversation. Also, sleep is disturbed, with a tendency to early morning waking, so that such persons are at their worst in the morning, both in spirit and in energy output. Their tendency is to improve as the day wears on, and they may even feel fairly normal by evening. It may be difficult to decide whether the fatigue is a primary manifestation of the disease or secondary to a lack of interest.

Among chronically fatigued individuals without medical disease, not all deviate enough from normal to justify the diagnosis of anxiety or depression. Many persons, because of circumstances beyond their control, have little motivation and much idle time. They are bored with the monotony of their routine. Such circumstances are conducive to fatigue, just as the opposite, a strong emotion or a new enterprise that excites optimism and enthusiasm, will dispel fatigue. Some persons are born with low impulse and energy and become more so at times of stress; they have a lifelong inability to exercise vigorously, to compete successfully, to work hard without exhaustion, to withstand illness or recover quickly from it, or to assume a dominant role in a social group—a “constitutional asthenia” (Kahn’s term). Most of these traits are evident from childhood. These difficulties are not currently framed in these terms because they sound judgmental, but disorders of this type have been known since antiquity and only vary in name and social context in each era.

Fatigue in Neurologic Diseases

Not unexpectedly, fatigue and intolerance of exercise (i.e., fatigue with mild exertion) are prominent manifestations of myopathic disease. Even in myasthenia gravis, the muscles exhibiting fatigue are usually weak, however, in the resting state. In addition to myasthenia gravis, the classes of myopathy in which weakness, inability to sustain effort, and excessive fatigue are notable features include the muscular dystrophies, congenital myopathies, other disorders of neuromuscular transmission (Lambert-Eaton syndrome), toxic myopathies (e.g., from cholesterol-lowering drugs), some of the glycogen storage myopathies, and mitochondrial myopathies. One type of glycogen storage disease, McArdle phosphorylase deficiency, is exceptional in that fatigue and weakness are accompanied by pain and sometimes by cramps and contracture. The first contractions after rest are of near-normal strength, but after 20 to 30 contractions, there occurs a deep ache and an increasing firmness and shortening of the contracting muscles. Another such process, acid maltase deficiency, is at times associated with disproportionate weakness and fatigue of respiratory muscles, which leads to dyspnea and retention of carbon dioxide. The characteristics of these diseases are presented in the chapters on muscle disease. Further comments on muscular fatigue can be found in Chap. 48.

Fatigue of varying degree is also a regular feature of all diseases that are marked by denervation of muscle and loss of muscle fibers. Fatigue in these cases is a result of the excessive work imposed on the remaining intact muscle (overwork fatigue). This is most characteristic of amyotrophic lateral sclerosis and the postpolio syndrome, but it also occurs in patients who are recovering from Guillain-Barré syndrome and in those with chronic polyneuropathy.

Not surprisingly, many neurologic diseases that are characterized by incessant muscular activity or by difficulty engaging the muscles (Parkinson disease, cerebral palsy, Huntington disease, hemiballismus) also induce fatigue. Muscles partially paralyzed by a stroke feel tired and may cause an overall fatigue state. The distinguished neuroanatomist A. Brodal gave an interesting account of his own stroke and its effects on muscle power. Fatigue is often a major complaint of patients with multiple sclerosis; its cause is unknown, although the effect of cytokines circulating in the cerebrospinal fluid has been postulated. The depression that follows stroke or myocardial infarction frequently presents with the complaint of fatigue rather than other signs of mood disorder. Inordinate fatigue is a common complaint among patients with postconcussive syndrome (see Chap. 35). Severe fatigue that causes the patient consistently to go to bed right after dinner and makes all mental activity effortful should suggest an associated depression. These central fatigue states and their possible mechanisms, almost all speculative, have been discussed by Chaudhuri and Behan.

Many states of disordered autonomic function in which static or orthostatic hypotension are features, are associated with a fatigue state. Whether there is in addition a type of central autonomic (hypothalamic) fatigue, aside from the endocrine changes discussed below, is uncertain, but such an entity seems plausible and has been included in models of the illness currently called chronic fatigue syndrome.

Fatigue in Medical Diseases

A wide variety of medications and other therapeutic agents, particularly when first administered, sometimes induce fatigue. The main offenders in this respect are antihypertensive drugs, especially beta-adrenergic blocking agents, antiepileptics, antispasticity drugs, anxiolytics, chemotherapy and radiation therapy and, paradoxically, many antidepressant and antipsychotic drugs. Introduction of these medications in gradually escalating doses may obviate the problem, but just as often, an alternative medicine must be chosen. The administration of beta-interferon for the treatment of multiple sclerosis (and alpha-interferon for other diseases) induces fatigue of varying degree. Surgeons and nurses can testify to fatigue that comes with exposure to anesthetics in inadequately ventilated operating rooms. Similarly, fatigue and headache may result from exposure to carbon monoxide or natural gas in homes with furnaces in disrepair or from leaking gas pipes, but this is also a frequent delusion in anxious, depressed, or demented patients.

The sleep apnea syndrome is an important and often overlooked cause of fatigue and daytime drowsiness. In overweight men who snore loudly and need to nap frequently, testing for sleep apnea is indicated (this subject was taken up in Chap. 19). Correcting the obstructive apnea that underlies this condition leads to a dramatic reduction in fatigue. The same holds for patients who have neuromuscular diseases that affect the diaphragm and other respiratory muscles.

Acute or chronic infection is an important cause of fatigue. Everyone has at some time or other sensed the abrupt onset of exhaustion, a tired ache in the muscles, or an inexplicable listlessness, only to discover later that he was “coming down with the flu.” Chronic infections such as hepatitis, tuberculosis, brucellosis, infectious mononucleosis, HIV, and bacterial endocarditis may not be evident immediately but should be suspected when fatigue is a new symptom and disproportionate to other symptoms such as mood change, nervousness, and anxiety. Whether a chronic form of Lyme disease is responsible for chronic fatigue, as often imputed, is uncertain at best. Often, fatigue begins with an obvious infection (such as influenza, hepatitis, or infectious mononucleosis), but persists for several weeks after the overt manifestations of infection have subsided; it may then be difficult to decide whether the fatigue represents the lingering effects of the infection or is due to psychologic-asthenic symptoms during convalescence. This difficult problem is discussed below. Patients with systemic lupus, Sjögren syndrome, or polymyalgia rheumatica may complain of severe fatigue; in the last of these, fatigue may be the initial and a profound symptom.

Metabolic and endocrine diseases of various types may cause inordinate degrees of lassitude and fatigue. Sometimes there is, in addition, a true muscular weakness. In Addison, Sheehan, and Simmonds diseases, fatigue may dominate the clinical picture. Aldosterone deficiency is another established cause of chronic fatigue. In persons with hypothyroidism with or without frank myxedema, lassitude and fatigue are frequent complaints, as are muscle aches and joint pains. Fatigue may also be present in patients with hyperthyroidism, but it is usually less troublesome than nervousness. Uncontrolled diabetes mellitus is accompanied by excessive fatigability, as are hyperparathyroidism, hypogonadism, and Cushing disease. Fatigue as a feature of vitamin B12 deficiency, as stated in many textbooks, has not been evident in the cases with mild deficiency that we have observed.

Reduced cardiac output and diminished pulmonary reserve are important causes of breathlessness and fatigue, which are brought out by mild exertion. Anemia, when severe, is another cause, probably predicated on a similar inadequacy of oxygen supply to tissues. Mild grades of anemia are usually asymptomatic, and tiredness is still far too often ascribed to it. An occult malignant tumor, e.g., pancreatic, hepatic, or gastric carcinoma, may announce itself by inordinate fatigue. In patients with metastatic carcinoma, and especially lymphoma, leukemia, or multiple myeloma, fatigue is a usual and prominent symptom. Uremia is accompanied by fatigue; the associated anemia may play a role. Any type of nutritional deficiency may, when severe, cause lassitude; in its early stages, this may be the chief complaint. Weight loss and a history of alcoholism and dietary inadequacy provide the clues to the nature of the illness.

Pregnancy causes fatigue, which may be profound in the later months. To some extent the underlying causes, including the work of carrying excess weight and an anemia, are obvious; but if excessive weight gain and hypertension are associated, preeclampsia should be suspected.

Postviral and Chronic Fatigue Syndromes

A particularly difficult problem arises in the patient who complains of severe fatigue for many months or even years after a bout of infectious mononucleosis or some other viral illness. This has been appropriately called the postviral fatigue syndrome. The majority of patients are women between 20 and 40 years of age, but there are undoubtedly young men with the same illness. A few such patients had been found to have unusually high titers of antibody to Epstein-Barr virus (EBV), which suggested a causal relationship and gave rise to terms such as the chronic infectious mononucleosis or chronic EBV syndrome (Straus et al). However, subsequent studies made it clear that a majority of patients with complaints of chronic fatigue have neither a clear-cut history of infectious mononucleosis nor serologic evidence of this or another infection (Straus; Holmes et al). In some of these patients, the fatigue state has allegedly been associated with obscure immunologic abnormalities similar to those attributed (spuriously) to silicone breast implants or minor trauma. The currently fashionable designation for these abstruse states of persistent fatigue is the chronic fatigue syndrome.

Some perspective is provided by the recognition that a malady of this precise nature, under many different names, has long pervaded postindustrial western society, as described by Shorter in an informative history of the chronic fatigue syndrome. The attribution of fatigue to viral or Lyme infection and to ill-defined immune dysfunction are only the latest in a long line of putative explanations. At various times, even in our recent memory, colitis and other forms of bowel dysfunction, spinal irritation, hypoglycemia, brucellosis, and chronic candidiasis, “multiple chemical sensitivity,” retroviral infection, or environmental allergies, among others, have been proposed without basis as causes. Unfortunately, these spurious associations have only served to marginalize the disease and patients who suffer from it.

The current criteria for the diagnosis of chronic fatigue syndrome are the presence of persistent and disabling fatigue for at least 6 months, coupled with an arbitrary number (6 or 8) of persistent or recurrent somatic and neuropsychologic symptoms including low-grade fever, cervical or axillary lymphadenopathy, myalgias, migrating arthralgias, sore throat, forgetfulness, headaches, difficulties in concentration and thinking, irritability, and sleep disturbances (Holmes et al). A number of such patients in our experience have complained of paresthesias in the feet or hands. On close questioning, many of these sensations prove to be odd, particularly numbness in the bones or muscles or fluctuating patches of numbness or paresthesia on the chest, face, or nose. Unusual descriptions may be given if the patient is allowed adequate time to describe the symptoms. A few have reported blurred or “close to” double vision; in neither case are there physical findings to corroborate the sensory experiences.

There is a common association with the similarly obscure entity of fibromyalgia, consisting of neck, shoulder, and paraspinal pain and point tenderness, as described in Chaps. 11 and 48. Despite these complaints, the patient may look surprisingly well and the neurologic examination is normal. The term for this same entity, myalgic encephalomyelitis, is preferred in Great Britain and captures the association between the two syndromes.

Complaints of muscle weakness are also frequent among such patients, but Lloyd and coworkers, who studied their neuromuscular performance and compared them with control subjects, found no difference in maximal isometric strength or endurance in repetitive submaximal exercise and no change in intramuscular acidosis, serum creatine kinase (CK) levels, or depletion of energy substrates. These individuals share with depressed patients a subnormal response to cortical magnetic motor stimulation after exercise (Samii et al), which can be said to match their symptoms of reduced endurance but otherwise is difficult to interpret. In a small number of affected persons, a chronic but usually mild hypotension, elicited with tilt-table testing and reversed by mineralocorticoids, has been proposed as a cause of chronic fatigue (Rowe et al). Electromyography and nerve conduction studies are typically normal, as is the spinal fluid, but the electroencephalogram (EEG) may be mildly and nonspecifically slowed. Batteries of psychologic tests have disclosed variable impairments of cognitive function, misinterpreted by advocates of the “organic” nature of the syndrome as proof of some type of encephalopathy.