S2
BACKGROUND
History of Chronic Fatigue Syndrome Stephen E. Straus
From the Medical Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
In April 1987, a working group convened by the Division of Viral Diseases of the Centers for Disease Control arrived at a tentative consensus regarding the clinical features of the chronic fatigue syndrome (CFS). That meeting and the subsequent publication of its research definition were the culmination of intensive efforts on the part of a variety of groups to clarify the nature of the syndrome [1]. It had become apparent during the preceding several years that chronic fatigue, particularly when occurring in concert with other somatic complaints, is a common and debilitating problem. That these symptoms often elude specific diagnosis and appear to occur in clusters led to concern that CFS represents a new and unique problem. It is my goal to review briefly the history of CFS. In so doing, it becomes apparent that CFS is not of recent origin. Physicians struggled to define it for centuries in the context of their own comprehension of human pathophysiology. Many names have been given to it, each reflecting a particular concept of the syndrome's etiology and epidemiology. Most evident throughout the history of this syndrome is the debate about the relative contribution of organic and psychological factors to the disease process of CFS. The past few years have witnessed a renewed interest in this syndrome. Recent studies linked CFS with virologic and immunologic problems. Still others emphasized the syndrome's high prevalence and its ability to spread epidemically and reasserted its considerable psychiatric comorbidity. Yet, there remains no satisfactory hypothesis on its cause and little more than anecdotal evidence regarding its treatment.
Febricula In 1750, Sir Richard Manningham published a treatise on febricula (figure 1), describing its features as including: "lit-
Please address request for reprints to Dr. Stephen E. Straus, Building 10, Room IIN113, National Institutes of Health, Bethesda, Maryland 20892. Reviews of Infectious Diseases 1991;13(8uppll):S2-7 This article is in the public domain.
tle low, continued fever, . . . little transient chilliness . . . listlessness with great lassitude and weariness all over the body . . . little flying pains . . . sometimes the patient is a little delirious and forgetful" [2]. Manningham noted similar descriptions in the writings of Hippocrates and others among his eminent predecessors. He considered the syndrome to be most prevalent among women of wealthy families and those who are sedentary and studious and to be precipitated by antecedent causes, including grief, intense thoughts, and taking cold. It is not apparent how widely accepted the term febricula was. Manningham indicated there to be several synonymous diagnoses: hypo, spleen, fever on the spirits, nervous fever, hysteric fever, and the vapors.
Neurasthenia In the first half of the 19th century, the renowned clinician Austin Flint used the term nervous exhaustion to describe chronic fatigue. Although this became a widely popularized diagnosis, George Beard, an early neurologist, believed it to be inadequately scientific and, hence, coined the term neurasthenia to signify the lack of strength of the nerves that he believed to underlie the chronic fatigue [3]. Beard, acknowledging the need to distinguish neurasthenia from anemia and other recognizable causes of exhaustion, stated: "The diagnosis of the neurasthenic condition is sometimes entirely clear, and again is quite difficult. The diagnosis is obtained partly by positive symptoms, and partly by exclusion" [3]. Beard realized that a wide variety of insults to the nervous system trigger neurasthenia and that its prognosis is as variable as those inciting factors. "Acutecases resulting from acute disease, usually recover rapidly, but sometimes become chronic, especially when the prior disease has been long and exhausting" [3]. Beard's concept of neurasthenia and his books describing it were embraced eagerly by the educated classes ofAmerica and Europe. Moreover, they had an enormous impact on the fledgling discipline of psychiatry, many of whose major
Downloaded from http://cid.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 13, 2015
Chronic fatigue syndrome is not a new medical condition. For centuries its confusing array of features has been attributed to numerous environmental, metabolic, infectious, immunologic, and psychiatric disturbances. This is a review and critique of many of these alternative diagnoses, sufficient to provide a historical background for current thinking about the disorder.
RID 1991;13 (Suppl 1)
History of CFS
figures, including Bleuler, Freud, and Kraepelin, attempted to accommodate the concept. By the third decade of the 20th century the prevailing opinion was that neurasthenia could not be distinguishedfrom affectivedisease, and the diagnosis lost favor.
DaCosta's (Effort) Syndrome Shortly after Beard'swork, DaCosta published his decadelong study of exhaustion in battle-worn soldiers of the Civil War [4]. DaCosta described a syndrome of fatigue, breathlessness, palpitations, dizziness, and chest pain. Headache, digestivedisturbances, and difficultysleepingwere common.
Most often the syndrome was precipitated acutely by febrile illnesses or gastroenteritis; occasionally, severe exertion was the proximate cause. On the basis of extensive examinations, DaCosta concluded that the syndrome was caused by an "irritable heart,"but he could not find evidence of structural abnormalities of the heart even after autopsy of patients who died of other causes. In a statement that presaged much more recent work, DaCosta stated his belief that the syndrome revealed "the connection between functional derangement and organic change" [4]. DaCosta's syndromeunderwentseveraltransformations between its description in 1871 and its ultimate rejection as a discrete entity in the 1940s [5-7]. During the first decades of the 20th century, DaCosta's syndrome was called the effort syndrome, neurocirculatory asthenia, and the autonomic imbalance syndrome. As summarizedby Wood in his Goulstonianlecturesof 1941 to the Royal College of Physiciansof London, DaCosta's syndrome was seen as occurring primarily in young adults but as also occurring in children [5-7]. Among civilians with the syndrome, there was a twofoldto threefoldpreponderance of women and a preponderance among those engaged in light work rather than in the manual trades. DaCosta's syndrome was common. For example, it was documented to have placed a measurable burden on Britain's military effort in World War I. About 60,000 cases were diagnosed among the British forces, and among those with the diagnosis, 44,000 received medical pensions [8]. Wood conducted extensive investigations of patients with DaCosta'ssyndromeand, havingdone so, wasunableto verify claims of cardiac, circulatory, or autonomic problems in its victims [6]. He therefore rejected the existence of a somatic basis for the syndrome, concluding instead that "patients shouldbe informed of the nature of their illness and be treated as psychoneurotics" [6]. Quite differentresults were reported by Cohen et al. in their study of 144 patients [9]. They observed significant differencesbetweenpatientsand controlsin ventilation, oxygen consumption, and lactate production during graded exercise. Although psychologictests placed most patients in the neurosis category, the conclusion was that the disease is physiologically based.
Chronic Brucellosis In 1934an American physician, Alice Evans, reported her impression that bacteria of the Brucella genus cause chronic infection and that one possible manifestation of the infection wasa largely subjectivesyndromeof chronic fatigue [10]. For nearly a quarter of a century after her proposal, the diagnosis of chronic brucellosis was made frequently. In some severe chronicinfections, Brucella couldbe recovered from the blood, bone, or other involvedtissues. In patients who had only subjective complaints, such as chronic fatigue, active bacterial
Downloaded from http://cid.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 13, 2015
Figure 1. Frontispiece from Sir Richard Manningharn's text on febricula published in 1750 [2] (courtesy of the National Library of Medicine).
S3
54
Straus
marily reflect a greater degree of propensity to become depressed rather than actual clinical depression in the group that remain symptomatic longer followingthe acute influenza"[13]. Hypoglycemia Hypoglycemia is a term that degenerated from its precise scientific meaning as it crept into common parlance. Many people casually attribute the familiar wave of late-afternoon fatigue to hypoglycemia. Through the 1960s and 1970s, persisting fatigue was increasingly attributed to hypoglycemia as well. Comment was made in 1974 on the legions of patients who pursued this endocrinologic basis for their exhaustion [14]. Convinced that dips in blood sugar to the 40- to 50-mg/dL range implied pathology, these patients were satisfied to consider themselves hypoglycemic and in need of elaborate dietary and behavioral modification. It is relatively trivial to dismiss the validity of hypoglycemia as a common cause of protracted fatigue. Careful studies have shown that wide fluctuations in fasting or postprandial blood sugars are compatible with normal health and do not often correlate with symptoms of fatigue. Yager and Young proposed that the fatigued patients possess "non-disease," namely, that which afflicts individuals in whom normal variations in laboratory tests are misinterpreted [15]. The similar misinterpretation of serologic test results led to the common belief in the 1940s and 1950s that the presence of antibodies in the blood to brucella antigens implies active brucellosis. Today, similar confusion exists regarding the meaning of antibodies to candida and Epstein-Barr virus antigens (see below).
Total Allergy Syndrome There exists today a subculture of individuals whose ill health is attributed to volatile and toxic environmental irritants and allergens. Practitioners and students of clinical ecology champion this hypothesis and evaluate and manage in imaginative, unorthodox, and costly ways patients who might have such problems. Clinical ecologists diagnose the problem as "total allergy syndrome" or "20th century disease" [16-19]. Patients are dispensed ostensibly neutralizing solutions to counteract the allergens and are instructed to follow elaborate diets in which many foodstuffs are excluded, while other foods are used in a rotating order to avoid frequent exposures to them. Moreover, these patients are relegated to living in havens designated as more ecologically safe in which the air, water, and furnishings are properly chosen or treated [19]. Stewart and Raskin performed detailed psychiatric evaluations of 18 people who were referred to them with the "2Oth century disease" [16]. Of these, 10 were found to be psychotic, anxious, or depressed and seven exhibited somatoform disorders. The investigators concluded that "psychiatric diagnoses
Downloaded from http://cid.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 13, 2015
infection could not be documented. The diagnosis was based solely on clinical impression. Several studies addressed the validity of Evans's hypothesis, including one conducted by Spink in Minneapolis [11]. In that investigation 65 patients were followed after episodes of proven acute brucellosis. Ten of these patients recovered completely in 1 year. Ofthe patients whose illness persisted for >1 year, bacteriologic evidence of continued infection was possible in 17and no organic cause of fatigue was demonstrable in 13. On psychiatric consultation, seven of these 13 proved to be "so maladjusted emotionally that diagnoses of severe psychoneurosis or psychopathic personality were made .... Some of the individuals had clear cut emotional problems prior to the onset of brucellosis" [11]. It was Spink's belief, then, that "patients bordering on a personality disorder or emotional disturbance may be tipped over into a functional state of chronic ill health by an attack of acute brucellosis" [11]. In a more thorough and related appraisal of the problem, Imboden and his colleagues at Johns Hopkins performed psychological tests of 24 individuals who had suffered confirmed acute brucella infections [12]. Test results were compared for groups of those who recovered completely from acute infection (eight patients), those who had recovered from chronic fatigue that began with acute brucellosis (six patients), and those who remained chronically fatigued nonetheless (10 patients). Both the group of patients who recovered from chronic illness and the group of patients who remained symptomatic were found on psychiatric evaluation to have more evidence of emotional disturbance than the group of patients who recovered acutely; the most severe abnormalities were in those who were still symptomatic. The investigators concluded "that the emotional disturbance is not merely secondary to the stress of illness, but is more critically related to the pre-illness personality structure" [12]. The studies of Spink and Imboden and their colleagues ended speculation about brucellosis as a direct cause of chronic fatigue in the absence of continued infection. The recognition that patients who remain fatiguedafter acute brucellosis differ psychologically from those who recover quickly led to the obvious question as to which came first, the illness or the neurosis. In other words, do some acute infections make one neurotic or does neurosis prolong symptoms of the illness? To pursue this question, the investigators at Johns Hopkins conducted a landmark study that proved that premorbid personality features influence the duration of perceived illness. Todo so, they evaluated military personnel infected during the Asian influenza epidemic of 1957 [13]. Detailed psychological tests conducted before the epidemic showed that the prevalence of psychoneurotic, particularly depressive, traits was greater in those who ultimately took >3 weeks to recover from influenza than in those who took
BACKGROUND
History of Chronic Fatigue Syndrome Stephen E. Straus
From the Medical Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
In April 1987, a working group convened by the Division of Viral Diseases of the Centers for Disease Control arrived at a tentative consensus regarding the clinical features of the chronic fatigue syndrome (CFS). That meeting and the subsequent publication of its research definition were the culmination of intensive efforts on the part of a variety of groups to clarify the nature of the syndrome [1]. It had become apparent during the preceding several years that chronic fatigue, particularly when occurring in concert with other somatic complaints, is a common and debilitating problem. That these symptoms often elude specific diagnosis and appear to occur in clusters led to concern that CFS represents a new and unique problem. It is my goal to review briefly the history of CFS. In so doing, it becomes apparent that CFS is not of recent origin. Physicians struggled to define it for centuries in the context of their own comprehension of human pathophysiology. Many names have been given to it, each reflecting a particular concept of the syndrome's etiology and epidemiology. Most evident throughout the history of this syndrome is the debate about the relative contribution of organic and psychological factors to the disease process of CFS. The past few years have witnessed a renewed interest in this syndrome. Recent studies linked CFS with virologic and immunologic problems. Still others emphasized the syndrome's high prevalence and its ability to spread epidemically and reasserted its considerable psychiatric comorbidity. Yet, there remains no satisfactory hypothesis on its cause and little more than anecdotal evidence regarding its treatment.
Febricula In 1750, Sir Richard Manningham published a treatise on febricula (figure 1), describing its features as including: "lit-
Please address request for reprints to Dr. Stephen E. Straus, Building 10, Room IIN113, National Institutes of Health, Bethesda, Maryland 20892. Reviews of Infectious Diseases 1991;13(8uppll):S2-7 This article is in the public domain.
tle low, continued fever, . . . little transient chilliness . . . listlessness with great lassitude and weariness all over the body . . . little flying pains . . . sometimes the patient is a little delirious and forgetful" [2]. Manningham noted similar descriptions in the writings of Hippocrates and others among his eminent predecessors. He considered the syndrome to be most prevalent among women of wealthy families and those who are sedentary and studious and to be precipitated by antecedent causes, including grief, intense thoughts, and taking cold. It is not apparent how widely accepted the term febricula was. Manningham indicated there to be several synonymous diagnoses: hypo, spleen, fever on the spirits, nervous fever, hysteric fever, and the vapors.
Neurasthenia In the first half of the 19th century, the renowned clinician Austin Flint used the term nervous exhaustion to describe chronic fatigue. Although this became a widely popularized diagnosis, George Beard, an early neurologist, believed it to be inadequately scientific and, hence, coined the term neurasthenia to signify the lack of strength of the nerves that he believed to underlie the chronic fatigue [3]. Beard, acknowledging the need to distinguish neurasthenia from anemia and other recognizable causes of exhaustion, stated: "The diagnosis of the neurasthenic condition is sometimes entirely clear, and again is quite difficult. The diagnosis is obtained partly by positive symptoms, and partly by exclusion" [3]. Beard realized that a wide variety of insults to the nervous system trigger neurasthenia and that its prognosis is as variable as those inciting factors. "Acutecases resulting from acute disease, usually recover rapidly, but sometimes become chronic, especially when the prior disease has been long and exhausting" [3]. Beard's concept of neurasthenia and his books describing it were embraced eagerly by the educated classes ofAmerica and Europe. Moreover, they had an enormous impact on the fledgling discipline of psychiatry, many of whose major
Downloaded from http://cid.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 13, 2015
Chronic fatigue syndrome is not a new medical condition. For centuries its confusing array of features has been attributed to numerous environmental, metabolic, infectious, immunologic, and psychiatric disturbances. This is a review and critique of many of these alternative diagnoses, sufficient to provide a historical background for current thinking about the disorder.
RID 1991;13 (Suppl 1)
History of CFS
figures, including Bleuler, Freud, and Kraepelin, attempted to accommodate the concept. By the third decade of the 20th century the prevailing opinion was that neurasthenia could not be distinguishedfrom affectivedisease, and the diagnosis lost favor.
DaCosta's (Effort) Syndrome Shortly after Beard'swork, DaCosta published his decadelong study of exhaustion in battle-worn soldiers of the Civil War [4]. DaCosta described a syndrome of fatigue, breathlessness, palpitations, dizziness, and chest pain. Headache, digestivedisturbances, and difficultysleepingwere common.
Most often the syndrome was precipitated acutely by febrile illnesses or gastroenteritis; occasionally, severe exertion was the proximate cause. On the basis of extensive examinations, DaCosta concluded that the syndrome was caused by an "irritable heart,"but he could not find evidence of structural abnormalities of the heart even after autopsy of patients who died of other causes. In a statement that presaged much more recent work, DaCosta stated his belief that the syndrome revealed "the connection between functional derangement and organic change" [4]. DaCosta's syndromeunderwentseveraltransformations between its description in 1871 and its ultimate rejection as a discrete entity in the 1940s [5-7]. During the first decades of the 20th century, DaCosta's syndrome was called the effort syndrome, neurocirculatory asthenia, and the autonomic imbalance syndrome. As summarizedby Wood in his Goulstonianlecturesof 1941 to the Royal College of Physiciansof London, DaCosta's syndrome was seen as occurring primarily in young adults but as also occurring in children [5-7]. Among civilians with the syndrome, there was a twofoldto threefoldpreponderance of women and a preponderance among those engaged in light work rather than in the manual trades. DaCosta's syndrome was common. For example, it was documented to have placed a measurable burden on Britain's military effort in World War I. About 60,000 cases were diagnosed among the British forces, and among those with the diagnosis, 44,000 received medical pensions [8]. Wood conducted extensive investigations of patients with DaCosta'ssyndromeand, havingdone so, wasunableto verify claims of cardiac, circulatory, or autonomic problems in its victims [6]. He therefore rejected the existence of a somatic basis for the syndrome, concluding instead that "patients shouldbe informed of the nature of their illness and be treated as psychoneurotics" [6]. Quite differentresults were reported by Cohen et al. in their study of 144 patients [9]. They observed significant differencesbetweenpatientsand controlsin ventilation, oxygen consumption, and lactate production during graded exercise. Although psychologictests placed most patients in the neurosis category, the conclusion was that the disease is physiologically based.
Chronic Brucellosis In 1934an American physician, Alice Evans, reported her impression that bacteria of the Brucella genus cause chronic infection and that one possible manifestation of the infection wasa largely subjectivesyndromeof chronic fatigue [10]. For nearly a quarter of a century after her proposal, the diagnosis of chronic brucellosis was made frequently. In some severe chronicinfections, Brucella couldbe recovered from the blood, bone, or other involvedtissues. In patients who had only subjective complaints, such as chronic fatigue, active bacterial
Downloaded from http://cid.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 13, 2015
Figure 1. Frontispiece from Sir Richard Manningharn's text on febricula published in 1750 [2] (courtesy of the National Library of Medicine).
S3
54
Straus
marily reflect a greater degree of propensity to become depressed rather than actual clinical depression in the group that remain symptomatic longer followingthe acute influenza"[13]. Hypoglycemia Hypoglycemia is a term that degenerated from its precise scientific meaning as it crept into common parlance. Many people casually attribute the familiar wave of late-afternoon fatigue to hypoglycemia. Through the 1960s and 1970s, persisting fatigue was increasingly attributed to hypoglycemia as well. Comment was made in 1974 on the legions of patients who pursued this endocrinologic basis for their exhaustion [14]. Convinced that dips in blood sugar to the 40- to 50-mg/dL range implied pathology, these patients were satisfied to consider themselves hypoglycemic and in need of elaborate dietary and behavioral modification. It is relatively trivial to dismiss the validity of hypoglycemia as a common cause of protracted fatigue. Careful studies have shown that wide fluctuations in fasting or postprandial blood sugars are compatible with normal health and do not often correlate with symptoms of fatigue. Yager and Young proposed that the fatigued patients possess "non-disease," namely, that which afflicts individuals in whom normal variations in laboratory tests are misinterpreted [15]. The similar misinterpretation of serologic test results led to the common belief in the 1940s and 1950s that the presence of antibodies in the blood to brucella antigens implies active brucellosis. Today, similar confusion exists regarding the meaning of antibodies to candida and Epstein-Barr virus antigens (see below).
Total Allergy Syndrome There exists today a subculture of individuals whose ill health is attributed to volatile and toxic environmental irritants and allergens. Practitioners and students of clinical ecology champion this hypothesis and evaluate and manage in imaginative, unorthodox, and costly ways patients who might have such problems. Clinical ecologists diagnose the problem as "total allergy syndrome" or "20th century disease" [16-19]. Patients are dispensed ostensibly neutralizing solutions to counteract the allergens and are instructed to follow elaborate diets in which many foodstuffs are excluded, while other foods are used in a rotating order to avoid frequent exposures to them. Moreover, these patients are relegated to living in havens designated as more ecologically safe in which the air, water, and furnishings are properly chosen or treated [19]. Stewart and Raskin performed detailed psychiatric evaluations of 18 people who were referred to them with the "2Oth century disease" [16]. Of these, 10 were found to be psychotic, anxious, or depressed and seven exhibited somatoform disorders. The investigators concluded that "psychiatric diagnoses
Downloaded from http://cid.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 13, 2015
infection could not be documented. The diagnosis was based solely on clinical impression. Several studies addressed the validity of Evans's hypothesis, including one conducted by Spink in Minneapolis [11]. In that investigation 65 patients were followed after episodes of proven acute brucellosis. Ten of these patients recovered completely in 1 year. Ofthe patients whose illness persisted for >1 year, bacteriologic evidence of continued infection was possible in 17and no organic cause of fatigue was demonstrable in 13. On psychiatric consultation, seven of these 13 proved to be "so maladjusted emotionally that diagnoses of severe psychoneurosis or psychopathic personality were made .... Some of the individuals had clear cut emotional problems prior to the onset of brucellosis" [11]. It was Spink's belief, then, that "patients bordering on a personality disorder or emotional disturbance may be tipped over into a functional state of chronic ill health by an attack of acute brucellosis" [11]. In a more thorough and related appraisal of the problem, Imboden and his colleagues at Johns Hopkins performed psychological tests of 24 individuals who had suffered confirmed acute brucella infections [12]. Test results were compared for groups of those who recovered completely from acute infection (eight patients), those who had recovered from chronic fatigue that began with acute brucellosis (six patients), and those who remained chronically fatigued nonetheless (10 patients). Both the group of patients who recovered from chronic illness and the group of patients who remained symptomatic were found on psychiatric evaluation to have more evidence of emotional disturbance than the group of patients who recovered acutely; the most severe abnormalities were in those who were still symptomatic. The investigators concluded "that the emotional disturbance is not merely secondary to the stress of illness, but is more critically related to the pre-illness personality structure" [12]. The studies of Spink and Imboden and their colleagues ended speculation about brucellosis as a direct cause of chronic fatigue in the absence of continued infection. The recognition that patients who remain fatiguedafter acute brucellosis differ psychologically from those who recover quickly led to the obvious question as to which came first, the illness or the neurosis. In other words, do some acute infections make one neurotic or does neurosis prolong symptoms of the illness? To pursue this question, the investigators at Johns Hopkins conducted a landmark study that proved that premorbid personality features influence the duration of perceived illness. Todo so, they evaluated military personnel infected during the Asian influenza epidemic of 1957 [13]. Detailed psychological tests conducted before the epidemic showed that the prevalence of psychoneurotic, particularly depressive, traits was greater in those who ultimately took >3 weeks to recover from influenza than in those who took
