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Politics, Science and the Emergence of a New Disease

The Case of Chronic Fatigue Syndrome

LA Jason, JA Richman, F Friedberg, L Wagner, R Taylor, KM Jordan. American Psychologist, 1997, 52(9):973-983
©1997 American Psychological Association

Chronic fatigue syndrome (CFS) emerged as a diagnostic category during the last decade. Initial research suggested that CFS was a relatively rare disorder with a high level of psychiatric comorbidity. Many physicians minimized the seriousness of this disorder and also interpreted the syndrome as being equivalent to a psychiatric disorder. These attitudes had negative consequences for the treatment of CFS. By the mid 1990's, findings from more representative epidemiologic studies indicated considerably higher CFS prevalence rates. However, the use of the revised CFS case definition might have produced heterogeneous patient groups, possibly including some patients with pure psychiatric disorders. Social scientists have the expertise to more precisely define this syndrome and to develop appropriate and sensitive research strategies for understanding this disease.


Although the most significant symptom of Chronic Fatigue Syndrome (CFS) is chronic fatigue, it is accompanied by various combinations of other symptoms, including sore throats, muscle pains, unrefreshing sleep, and so on (Jason, Wagner et al. 1995). Wessely (1990) suggested that CFS has its origins in the last century, with the condition known as neurasthenia. By the late 1800s, neurasthenia was one of the most frequently diagnosed illnesses; however, by World War I, the diagnosis of neurasthenia almost disappeared. By the beginning of this century, medical skepticism concerning this illness increased, and neurasthenia began to be viewed as a psychiatric disorder rather than a neurological illness. In addition, neurasthenia patients were increasingly held in low esteem by medical personnel (Wessely, 1990). The debate that occurred about 100 years ago, concerning whether neurasthenia was a disease of the body or mind has reappeared with CFS (Friedberg & Jason, in press). This article examines this controversy by exploring how the establishment of diagnostic criteria and the design of early epidemiologic studies led to inaccurate and biased characterizations of CFS.


The Original Case Definition
The original case definition of CFS, published in Holmes et al. (1988), defined CFS as the "new onset of persistent or relapsing, debilitating fatigue" that was "severe enough to reduce or impair average daily activity below 50% of the patient's premorbid activity level for a period of at least six months" (p. 388). Other conditions that could produce similar symptoms needed to be excluded. In addition, a person had to have 8 or more of the 11 minor symptoms (e.g., sore throat, painful lymph nodes, unexplained generalized muscle weakness, etc.). However, use of the original case definition of CFS and the type and scoring of psychiatric tests appear to have produced erroneous estimates of the extent of CFS comorbidity with psychiatric disorders.

Psychiatric Comorbidity
In an influential review article, David, Wessely and Pelosi (1991) concluded that depression occurs in about 50% of CFS cases, and anxiety and other disorders (i.e., somatization, minor depression, phobia, or anxiety disorders) occur in about 25% of cases. These findings have led some to conclude that CFS is solely a psychiatric disorder. For example, Abbey and Garfinkel (1991) wrote, "Chronic fatigue syndrome will meet the same fate as neurasthenia -- a decline in social value as it is demonstrated that the majority of its sufferers are experiencing primary psychiatric disorders or psychophysiological reactions and that the disorder is often a culturally sanctioned form of illness behavior" (p. 1638). Although the majority of studies with CFS samples have found extremely high rates of psychiatric comorbidity (David et al., 1991), unfortunate biases were introduced by the criteria within the case definition.

A key problem with the original CFS criteria was that it required eight or more minor symptoms, which involve many unexplained somatic complaints. However, the requirement of a high number of unexplained somatic complaints can inadvertently select individuals with psychiatric problems (Straus, 1992). Katon and Russo (1992) classified 285 chronic fatigue patients into four groups, with each group having a higher number of unexplained somatic symptoms. Patients with the highest numbers of unexplained physical symptoms had extraordinary rates of psychiatric disorders. Patients in the group with the lowest number of unexplained symptoms displayed a prevalence of psychiatric symptoms similar to that reported for other clinic populations with chronic medical illnesses. The diagnostic criteria for CFS inadvertently selected subgroups of patients with high levels of psychiatric diagnoses.

In addition, Wood, Bentall, Gopfert, Dewey, and Edwards's (1994) study found no support for the hypothesis that CFS participants respond to stress with physical symptoms rather than by expressing feelings. Ray, Weir, Cullen, and Phillips (1992) found no significant relation between indexes of perceived CFS illness severity (e.g., frequency of symptoms, course of illness, disability, and severity of illness) and emotional distress. Moreover, the lack of an independent relationship between these two variables could be one of the bases on which people with CFS attribute their illness to physical rather than psychological causes. Finally, if people with CFS present physical complaints to mask their psychological problems, then according to Katon and Walker (1993), there should be an inverse relationship between the number of depression and anxiety symptoms and the number of reported somatic symptoms. However, this has not been found. Rather, people with CFS who become distressed report somatic, depression, and anxiety symptoms concurrently (Katon & Russo, 1992; Katon & Walker, 1993).

Problems in the Scoring and Selection of Psychiatric Instruments
The Diagnostic Interview Schedule (DIS; Robins & Regier, 1991), a structured psychiatric instrument designed for use in community surveys, has frequently been used to assess psychiatric comorbidity in CFS samples. Unfortunately, this instrument was not designed for use with medically ill populations. If a respondent mentions that a symptom on the DIS (e.g., pains in arms or legs) was due to a medical problem that was diagnosed by a physician, DIS rules indicate this problem should not be counted as a psychiatric problem. If the physician attributed the patient's symptoms to nerves or a psychiatric disorder, the patient automatically receives a score counting towards a psychiatric diagnosis, regardless of whether or not the patient agrees with the physician. Also, if several physicians diagnosed a patient as having a medical disorder, but only one attributed the symptom to a psychiatric disorder, the item would be scored to count towards a psychiatric diagnosis. Many physicians still do not accept CFS as a legitimate medical disorder, so it is possible that many patients would have had at least one physician who diagnosed their medical complaints as being a psychiatric disorder, thus increasing the likelihood that people with CFS would receive a psychiatric diagnosis.

Many of the CFS minor symptoms are contained in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (American Psychiatric Association, 1994) categories. When Demitrack (1993) excluded symptoms attributable to CFS, 6 of 30 patients reported a lifetime history of major depression; however, when using criteria that included all symptoms, 12 of 30 patients reported a lifetime history of major depressive illness. Johnson, DeLuca, and Natelson (1996) found that changing the attribution of somatization symptoms from psychiatric (if the health care professional gave the symptom the following explanations: stress, anxiety, depression, "nerves," etc.) to physical (CFS symptoms were not coded as psychiatric) dramatically affected the rates of diagnosing somatization in a sample of CFS patients (rates ranged from 0 to 98% depending on whether CFS symptoms were coded as being due to a physical illness).

Some CFS investigators (e.g., Friedberg & Krupp, 1994) have used the semi-structured clinical interview (SCID; Robins, Helzer, Cotler, and Goldring, 1989) to assess psychiatric illnesses (Spitzer et al., 1988). In contrast to the rigid interview structure of the DIS, the SCID uses open-ended questions and all potential sources of information to encourage a thorough description of the problems by the interviewee. Use of the SCID is also limited to highly trained clinicians. This instrument was used by Hickie, Lloyd, Wakefield, and Parker (1990), who found the premorbid prevalence of major depressive disorder to be 12.5% and overall psychiatric disorders to be 24.5% in a sample of CFS patients, rates that are no higher than general community estimates. Lloyd, Hickie, Boughton, Spencer, and Wakefield (1990) also used the SCID and found a past prevalence of major depressive disorders in 21% of patients with CFS and a past prevalence of overall psychiatric disorders in 39% of patients. These rates are higher than Hickie et al.'s (1990) estimates but not nearly as high as rates from studies using the DIS. A study by Taylor and Jason (in press) administered the DIS and the SCID to a CFS sample. Of individuals diagnosed with CFS, 50% received a current Axis I psychiatric diagnosis when using the DIS; however, only 22% received a current Axis I diagnosis when using the SCID. These findings suggest that high or low psychiatric rates in CFS samples may be a function of whether symptoms are attributed to psychiatric or non-psychiatric causation.


Flawed Epidemiology
In 1994, the Centers for Disease Control (CDC) published a brochure titled The Facts about CFS, which estimated the prevalence of CFS to be from 4 to 10 cases per 100,000 people (or less than 19,000 adults in the United States, on the basis of the number of people in the United States who are 18 years of age or older [193,650,000]; U.S. Bureau of the Census, 1994). These rates would appear to be discrepant from the unusually high number of telephone calls (up to 3,000 a month) that the CDC had been receiving from people requesting information about CFS (McCluskey, 1993, p. 288). If CFS epidemiologic studies had, in fact, underestimated the number of people afflicted with this disease, this is highly problematic in terms of the adequacy of the public health response to this disorder.

The first and widely publicized study of CFS epidemiology, from which the estimates above were derived, was initiated in the late 1980s by the CDC (Gunn, Connel, & Randall, 1993). Investigators used a modified version of Holmes et al.'s (1988) criteria, and requested physicians in four cities to identify their patients who had a group of specified fatigue-related symptoms. The minimal prevalence rates of CFS ranged from 2.0 to 7.3 individuals per 100,000 cases.

This CFS epidemiological study as well as others were based on physician referrals from hospital and community-based clinics. However, medical sociological studies have indicated that many low income individuals do not have access to the health care system (Mechanic, 1983), therefore, it is inappropriate to estimate prevalence estimates solely from treatment facilities. Disadvantaged minorities do manifest higher levels of chronic illness, and they are less likely to receive adequate care and be counted in epidemiological studies from treatment sources (Dutton, 1986). Finally, it is likely that many physicians who are skeptical of the disorder's existence will be less likely to make referrals in epidemiological studies (Richman, Flaherty, & Rospenda, 1994).

Given physician skepticism about CFS and consequent antagonism between CFS patients and the traditional medical establishment, many CFS patients have dropped out of the medical care system. Consequently, CFS epidemiological studies that have relied on referrals from physicians at medical clinics might not accurately estimate prevalence rates, and the individuals identified in these studies might not be representative of the population of ill patients. In addition, if medical personnel feel that CFS is a relatively rare disorder and it is primarily caused by psychiatric explanations, physicians might minimize or misinterpret the physical complaints of CFS patients, and this could lead to the unfortunate mistrust and lack of communications that has been reported between patients and medical personnel (Denz-Penhey & Murdoch, 1993).

In 1993, Jason and colleagues (Jason, Fitzgibbon, et al., 1993; Jason, Taylor et al., 1995) interviewed a random, community-based sample . Those individuals who self-reported having CFS or many of the symptoms of CFS were examined by a physician and interviewed by a psychiatrist to determine whether they met case criteria for CFS. The research team diagnosed 0.2% of the sample with current CFS, a number higher than one would have expected given rates from past epidemiological studies. This rate of 200 per 100,000 was over 10 times higher than the rate originally reported by the CDC. Other research suggested that CFS might even be more prevalent among nurses (Jason, Taylor, et al., 1993); health care professionals might represent high risk groups for developing CFS. Another CFS epidemiological study, which used a random sample, also found higher CFS rates than the original CDC study. Buchwald et al. (1995) found rates from 75-267 per 100,000 in a sample of individuals enrolled in a health maintenance organization.

Epidemiologists at the CDC have recently shifted all surveillance efforts to community-based population surveys, and they now estimate that the prevalence of CFS-like illness is between 76 and 233 per 100,000 people (estimates given in response to questions from House of Representatives Congressman John Porter, which were submitted to the CDC after appropriations hearings on March 9, 1995). On the basis of some of the more recent prevalence data, the CDC has recently added CFS to the Priority 1 New and Reemerging Infectious Diseases, indicating that CFS is now defined as a top CDC priority (other Priority 1 diseases include E.coli and tuberculosis).


The Revised CFS Case Definition
Australian researchers (Lloyd et al. 1990) proposed a less rigorous definition of CFS, and soon afterwards a group of British investigators (Sharpe et al., 1991) published a third set of CFS criteria. Both the Australian and British definitions were more lenient than the US definition in that they did not require 8 or more minor symptoms and pre-existing psychiatric disorders (with some exceptions, eg., schizophrenia) were not reasons for exclusions.

In the United States, there was considerable dissatisfaction with the original Holmes et al. (1988) case definition because of problems noted above and because it was being inconsistently applied by researchers. In 1994, a new CFS definition was published (Fukuda et al., 1994). In this new case definition, a person needed to experience chronic fatigue that had a new or definite onset; was not substantially alleviated by rest; was not the result of ongoing exertion; and that resulted in substantial reductions in occupational, social, and personal activities. In addition, anxiety disorders, somatoform disorders, and nonpsychotic or nonmelancholic depression existing prior to CFS onset were no longer exclusionary. In addition, there needed to be the concurrent occurrence of four or more minor symptoms (e.g.,sore throat, muscle pain, etc.).

Methodological Problems With a Broadened Definition
This new case definition requires only four minor symptoms (Fukuda et al., 1994), whereas the previous definition required eight minor symptoms (Holmes et al., 1988). The new definition of CFS does not exclude people who have purely psychosocial, stress, or many psychiatric reasons for their fatigue (K. Fukuda, personal communication, August 30, 1995) . By broadening the CFS definition, it is important to insure that those patients with solely a psychiatric disorder are not erroneously included within the CFS rubric. The issue of inappropriately including individuals with purely psychiatric disorders with the CFS diagnosis had been previously recognized. For example, Abbey, a member of the Physician Review Committee for the first CDC epidemiological study, said "It is clear to my psychiatrist's eye that they [some participants] do not have CFS, but rather primary psychiatric disorder which has been misdiagnosed" (as cited in Gunn et al., 1993, p. 97), and yet because of the decision tree being used, some of these participants were being counted as CDC-defined CFS with concurrent psychopathology (Gunn et al., 1993). Some individuals with CFS might have had psychiatric problems before and/or after CFS onset, or both, and yet some individuals, as noted by Abbey, have primary psychiatric disorders. Including the latter type of patients in the current CFS case definition could seriously complicate the interpretation of epidemiological and treatment studies. Major depressive disorder is an example of a primary psychiatric disorder, which has some overlapping symptoms with CFS.

CFS Versus Major Depression
Fatigue, sleep disturbances, and poor concentration occur in both depression and CFS. It is important to differentiate those with a principal diagnosis of major depressive disorder from CFS. This is particularly important because it is possible that some patients with major depressive disorder also have chronic fatigue and four minor symptoms that can occur with depression (e.g., unrefreshing sleep, joint pain, muscle pain, impairment in concentration). 1/ Fatigue and these four minor symptoms also are defining criteria for CFS. Is it possible that some patients with a primary affective disorder could be misdiagnosed as having CFS? Some CFS investigators would not see this as a confounding problem because they believe that high rates of psychiatric comorbidity indicate that CFS is mainly a psychiatric disorder. For example, Manu (as cited in Abbey, 1993) stated,

The difference [between CFS and neurasthenia] seems to be that in the 19th century, patients with neurasthenia were able to enjoy a physical diagnosis for about 30 years. Now, research demonstrating the high prevalence of major depression among these patients has taken the physical explanation away from them, by pointing out that this might simply be an affective disorder. (p. 252)

Several studies, however, clearly differentiated CFS from depression. For instance, CFS patients show more alpha electroencephalographic activity during non-REM sleep, but this is not seen in dysthymic or major depressive disorder (Whelton, Salit, & Moldofsky, 1992). Bakheit, Behan, Dinan, Gray, and O'Keane (1992) found up-regulation of hypothalamic 5-hydroxytryptamine receptors in patients with postviral fatigue syndrome but not in those with primary depression. Lutgendorf, Klimas, Antonini, Brickman, and Fletcher (1995) found that CFS patients with greater cognitive difficulties had more abnormalities in their immune system, with depression controlled for, suggesting that the presence of cognitive difficulties in CFS patients cannot be explained solely by depressive or mood disturbances.

Individuals with depressive disorders often experience anhedonia, a loss of pleasure, and feelings of worthlessness; symptoms that are usually not experienced by individuals with CFS, unless they have comorbid depression. When Wessely and Powell (1989) used the Hospital Anxiety and Depression Scale (devised for use with physically ill patients in which items for depression are based on the anhedonia state; Zigmond & Snaith, 1983), individuals with CFS scored between those with neuromuscular disorders and those with affective disorders. Thus, patients with CFS experience less pleasure than neuromuscular patients and more pleasure than those with depression. Stone et al. (1994) found that CFS patients did not differ from non-patients in overall levels of positive and negative affectivity, and this finding argues against an explanation of CFS as an expression of depression. Two comparative psychodiagnostic investigations of CFS, multiple sclerosis (MS) and clinical depression ( Johnson et al., 1996; Pepper, Krupp, Friedberg, Doscher, & Coyle, 1993) found that the CFS group more closely resembled the MS condition than the clinically depressed comparison group in terms of total personality disturbance and frequency of Axis 1 disorders.

Several CFS symptoms, including prolonged fatigue after physical exertion, night sweats, and sore throats, are not commonly found in depression. In addition, whereas fatigue is the principal feature of CFS, with depression it does not assume such prominence (Friedberg, 1996; Komaroff et al., 1996). Also, illness onset with CFS is often sudden, occurring in a few hours or days, whereas primary depression generally shows a more gradual onset. In summary, CFS and depression are two distinct disorders, although they share a number of common symptoms. Most importantly, the erroneous inclusion of people with primary psychiatric conditions in CFS samples will have detrimental consequences for the interpretation of both epidemiologic and treatment efficacy findings.

Simon Wessely and colleagues (Price, North, Wessely, & Fraser, 1992) used a version of the original CFS definition in an early epidemiologic study that found the prevalence rate of CFS to be 0.0074%, or 7.4 cases per 100,000. In a later epidemiologic study, Wessely, Chalder, Hirsch, Wallace, and Wright (in press) determined that 2.6%, or 2,600 per 100,000, of a primary health care setting sample had CFS, using the Fukuda et al. (1994) definition. It is of interest that these rates are within the range of several mood disorders. (Mood disorders are the most prevalent psychiatric disorders after anxiety disorders: For major depressive episode, the one-month prevalence is 2.2% and lifetime prevalence is 5.8%; Regier et al., 1988). In a relatively short period of time, Wessely and colleagues' (Price et al., 1992) estimates of the prevalence of CFS had changed markedly. One of the reasons that Wessely and colleagues' rates of CFS escalated, and are considerably higher than other recent epidemiologic studies (Lawrie & Pelosi, 1995), is that his team used the broadened Fukuda et al. definition of CFS. Individuals diagnosed with CFS in this epidemiologic study were subsequently compared with a sample of people with CFS who had been diagnosed from a hospital unit (Euba, Chalder, Deale & Wessely, 1995). Whereas 74% of the primary health sample had a previous psychiatric diagnosis before the onset of their fatigue, only 21% of the hospital sample had a previous diagnosis. The primary health sample had significantly worse mental health scores, and 59% felt their illness might be due to psychological or psychosocial causes (compared with 7% for the hospital sample). Wessely et al. (in press) did indicate that of the 2.6% with CFS, only 0.5% had no psychological disorder. In Wessely, Chalder, Hirsch, Wallace, and Wright's (1996) community based sample, 36 individuals were diagnosed as having CFS. Among this group, only 64% had sleep disturbances and 63% had postexertion malaise. These percentages are rather low, as both symptoms are critical features of CFS. Wessely and colleagues's finding of an increased prevalence of CFS reflects the use of the new Fukuda et al. case definition and possibly the inclusion of pure psychiatric cases with pure CFS disorders as well as true CFS disorders, which are also accompanied by psychiatric comorbidity.

In the Jason, Taylor et al. (1995) epidemiologic study, reviewed in the Flawed Epidemiology section, the initial screening telephone questionnaire would have identified 2.1% of the sample as having CFS based on the Fukuda et al. (1994) definition, a rate similar to Wessely et al.'s (in press). However, when those with alternative reasons for their fatigue were eliminated, on the basis on findings from the medical and psychiatric work-ups, then only 0.2% were identified with CFS. Using a broad or narrow definition of CFS will have important influences on CFS epidemiologic findings, and on rates of psychiatric comorbidity.


Findings from epidemiologic and diagnostic studies hold significant implications for treatment of CFS. Graded activity exercise schedules, where CFS patients are encouraged to gradually increase their daily activities, have been components of several cognitive-behavioral treatment studies. Burke et al. (1992) maintains that this approach is needed in order to help CFS patients overcome their disability. Friedberg (1996) maintains that this treatment would be appropriate if activity was avoided due to depressed mood and unrealistic fear of symptom flare-ups. However, for those CFS individuals who do not have psychologically mediated reductions in activity, such a directed approach would be inappropriate and perhaps counterproductive.

In an outcome study using a cognitive-behavioral intervention, Friedberg and Krupp (1994) found that depressed patients without CFS showed significant reductions in depression, stress, and severity scores. CFS subjects who reported more depressive symptoms showed significant reductions in symptoms of depression, stress, and fatigue severity, but their fatigue severity still remained abnormally high. In other words, even though the cognitive approach was effective in reducing catastrophic thinking and symptom magnification for the depressed CFS group, fatigue severity remained elevated. These findings are important because they suggest that for CFS patients, relieving the depression does not cure the fatigue symptoms. Friedberg and Krupp also found that there was no evidence that exercise avoidance had become a phobically mediated behavior. Friedberg and Krupp had to encourage many of their participants to rest rather than exert themselves and risk setbacks. They further noted that there appears to be an activity ceiling for individuals with CFS, and many were already performing near their ceiling (on the basis of self-report). If a graded activity schedule had been introduced beginning at their current baseline levels, many would have exceeded their activity threshold levels. Thus, instead of graded activity, Friedberg and Krupp assisted patients in rejecting obligations that previously exhausted them and encouraged them to devote more time to neglected premorbid activities (e.g., personal care, enjoyment, relaxation).

In a well-controlled Australian study, Lloyd et al. (1993) found that a cognitive-behavioral treatment program did not demonstrate a specific treatment effect with a CFS sample. In contrast, Sharpe et al. (1996) found that a cognitive-behavioral therapy program in Great Britain, including gradual and increasing increases in activity, did lead to sustained reduction in functional impairment in a sample of CFS patients (i.e., at a 12-month follow-up, 73% had a Karnofsky Scale [Karnofsky, Abelmann, Craver, & Burchenal, 1948] rating of 80 or more). 2/ A recent prestigious report from the Royal Colleges of Physicians, Psychiatrists, and General Practitioners (1996) in Great Britain stated that "the controlled increases in activity remain the corner stone of the management of CFS" (p. 24) and "rest per se is contraindicated in CFS" (p. 26).

The key question is why Sharpe et al. (1996) found significant reductions in levels of fatigue using a treatment strategy that Friedberg and Krupp (1994) claimed would have the opposite effect for CFS patients. It is possible that differences were in part due to Sharpe et al.'s (1996) focus on illness beliefs (i.e., unrealistic personal expectations were reviewed and attributions of symptoms to physical disease were questioned; Sharpe, 1996). However, in the Sharpe et al. (1996) study, the baseline Karnofsky Scale mean score was 71. (The Karnofsky Scale is a measure of patient functioning, and a score of 80 is within the range of normal functioning). In a study conducted in the United States with a severely ill CFS sample, the mean Karnofsky Scale score was 51 (Strayer et al. 1994). Thus, Sharpe et al.'s (1996) sample might have been less impaired than a severely ill group, and this is also suggested by their median duration of illness of 17 months. On the other hand, participants in Sharpe et al.'s (1996) study were primarily not working, and they spent 3.3 days in bed each week. These characteristics suggest that Sharpe et al.'s sample was more functionally impaired than patients seen in primary care but less chronically ill than those seen in tertiary care centers.

Differences in the conclusions drawn from the Friedberg and Krupp (1994) and Sharpe et al. (1996) outcome studies might be due to diagnostic differences underlying the samples recruited: A majority of the participants in the Frieberg and Krupp sample were employed either full or half time, and these high-functioning CFS patients who maintained employment and other activities may have already achived many of the goals of graded activity interventions. It is conceivable that included within the Sharpe et al. (1996) sample were individuals with moderate fatigue caused primarily by depression and other psychological factors rather than CFS (at study onset, 67% of the sample had an anxiety or depressive diagnosis, and 10% had a somatisation disorder). Because in the Sharpe et al. intervention, depression and anxiety scores were an important predictor of treatment outcome (Sharpe, 1996a), graded activity programs might be benefical to those disabled by psychiatric symptoms -- outcomes smilar to effective stepwise exposure treatments for severe phobia (Marks, 1987) and behavioral prescriptoipons for low-functioning depressed patients (Martison, 1987). 3/


Criteria from the original CFS case definition and biases in the scoring and selection of psychiatric tests contributed to high levels of psychiatric comorbidity with CFS. These findings might have contributed to physician beliefs that CFS was a predominantly psychiatric rather than medical disorder. In addition, flawed epidemiologic research significantly underestimated the community "true prevalence" of CFS. Relying on physician referrals for generating cases failed to take into consideration the negative bias of many physicians, and fewer referrals would be generated from those physicians who were skeptical of the existence of this illness. By the mid- 1990's, findings from epidemiologic studies with more valid sampling bases indicated considerably higher CFS prevalence rates. At the same time, however, a broadened definition of CFS might have produced more heterogeneous patient groups, complicating the interpretation of epidemiologic and treatment outcome data.

Fatigue, arbitrarily defined as more than 1 month in duration, is common in the general population, occurring between 19% and 28% of the population (Kroenke, Wood, Mangelsdorf, Meier, & Powell, 1988). However, severe fatigue is less common, with several studies suggesting that about 5% of a community sample would have significant fatigue for 6 months or more (Jason, Taylor et al., 1995; Pawlikowska et al., 1994). Among this 5% with chronic fatigue, a key question involves how many might be diagnosed with CFS, and rates range from 2.6% to less than 0.1%. A broad or narrow definition will have important influences on both CFS epidemiologic and treatment studies. Clearly, different CFS criteria account for some of this variability. In addition, some investigators believe that while CFS is probably a heterogeneous disorder, it is still possible to differentiate those having this discrete disorder from other psychiatric, fatigue producing conditions (Friedberg & Jason, in press). Other investigators, such as Wessely et al. (1996), believe that CFS represents an arbitrarily defined end point, and there are no clear cutoff points separating those with severe fatigue from CFS. These differences in theoretical conceptualizations of what constitutes CFS might also influence the diverse prevalence rates. More precise and clear definitions of CFS might help investigators reach more consensus on inclusionary and exclusionary criteria.

Over the past ten years, a series of key decisions were made concerning the criteria for CFS diagnosis and the selection of psychiatric instruments, which scored CFS symptoms as medical or psychiatric problems. At least some of these decisions may have been formulated within a societal and political context in which CFS was assumed to be a psychologically determined problem (Manu, Lane, & Matthews, 1988). Many physicians and researchers believed that CFS was similar to neurasthenia and that CFS would eventually have a similar fate once people recognized that most patients with this disease were really suffering from a psychiatric illness. Psychiatrists and physicians have also regarded fatigue as one of the least important of presenting symptoms (Lewis & Wessely, 1992). These biases have been filtered to the media, which has portrayed CFS in simplistic and stereotypic ways. For example, after the Sharpe et al. (1996) treatment study was published, British tabloids came out with headlines such as "ME's [the term for CFS in England] Mainly in the Mind: Study Reveals Yuppie Flu Can Be Cured by Positive Thinking" (1996). One major consequence is that many CFS patients feel dissatisfied with their medical care (David, et al., 1991) and have gone outside traditional medicine to be treated for their illness (Denz-Penhey & Murdoch, 1993; Jason, Ferrari, Taylor, Slavich, & Stenzel, 1996).

There are some medical illnesses that have been shown to elicit psychological disorders, and changes in mood, fatigue and malaise are commonly associated with infection (Ray, 1991). In addition, depression can be a reaction to a physical illness, as depression and anxiety are common in patients with cancer and heart disease. Depression that accompanies a prolonged illness may be better conceptualized as demoralization rather than a discrete psychiatric illness, particularly in ambiguous illnesses in which patients have difficulty gaining recognition that they have a legitimate nonpsychiatric illness (Ray,1991).

Throughout this article, the consequences resulting from the use of alternative criteria for selecting CFS cases have been emphasized. If inappropriate use of the case definition leads to the inclusion of individuals who only have a psychiatric condition, this heterogeneity of psychiatric and CFS patients will present difficulties in interpreting the results of epidemiologic and treatment studies. If individuals with chronic fatigue and some somatic symptoms are included with those who have sole psychiatric diagnoses, those with sole CFS diagnoses, and those who have some CFS and psychiatric comorbidity, these three groups need to be differentiated and analyzed separately as opposed to being collapsed into one category.

There are important implications of these findings for clinicians involved in the diagnosis and treatment of patients with CFS. When diagnosing CFS, it is important to distinguish CFS from other psychological disorders, particularly depression, generalized anxiety disorders, and somatization. It is beyond the scope of this paper to provide a comprehensive analysis of these differential diagnoses, as they are provided elsewhere (cf., Friedberg & Jason, in press); however, several general makers can be briefly mentioned. Patients with CFS differ from those with depression by more frequently having severe debilitating fatigue (100% vs. 28%, respectively), acute onset of the illness (84% vs. 0%, respectively), post-exertional malaise (79-87% vs. 19%, respectively), alcohol intolerance (60% vs. 21%, respectively), nausea (58% vs. 16%, respectively), and flu-like symptoms (43-65% vs. 10-22%, respectively; Friedberg & Jason, in press). CFS and generalized anxiety disorder share many symptoms (e.g., fatigue, difficulty concentrating, sleep disturbances, etc.), however, the most prominent symptom of generalized anxiety disorder is excessive, persistent worry, whereas the most prominent symptom of CFS is severe debilitating fatigue. Finally, whereas those with somatization disorder also have multiple somatic complaints, for CFS the primary feature of the illness is fatigue, whereas this is not the case with somatization (Friedberg, 1996).

Making recommendations for treatment is complicated given the research reviewed in this article. As mentioned earlier, graded exercise schedules, where CFS patients are encouraged to gradually increase their daily activities, have been recommended as a critical component of treatment programs by several CFS researchers (e.g., Burke, 1992; Sharpe et al., 1996 ). On the other hand, Friedberg and Krupp (1994) noted that many CFS patients are already performing near their activity ceiling, and if a graded activity schedule is introduced beginning at their current baseline levels, many would exceed their upper threshold levels. Given this controversy, it might be most prudent to evaluate each CFS patient individually. For those who are continually over-exerting themselves, they might need to be helped to stabilize or cut back and conserve their energy reserves, which might help them gain energy in the longer term. For those who are continually expending considerably less energy than they have available, they might be able to moderately and gradually increase their expended energy. What is critical is the development of tailor-made, individualized rehabilitation programs for the unique needs of each individual with CFS (Jason, King, Tryon, Frankenberry, & Jordan, 1997). In addition, if individuals with CFS have a comorbid psychiatric condition, like depression, it is important to treat the psychiatric disorder with well-evaluated, standardized treatment approaches. For example, Friedberg and Krupp (1994) found that cognitive-behavioral treatment was effective in reducing depression for those patients with depression and CFS.

In a recent validation study, Jason, Ropacki, et al. (1997) recruited four groups of participants (i.e., those with a diagnosis of CFS, lupus, or MS and a healthy control group). Using a screening scale that included the Fukuda et al. (1994) symptoms, every person in the sample who had CFS was correctly identified, but this set of symptoms also selected 27% of those with MS and 73% of those with lupus as having CFS. In other words, the screening scale, using the Fukuda et al. symptoms, is broad and can identify those with CFS but then also select many with other disorders. So, although the symptoms within the Fukuda et al. definition are adequate as an initial screen, additional medical and psychiatric information is necessary to exclude those with disorders other than CFS.

A significant complicating factor in understanding the dynamics of this illness is that there are probably different types of illnesses now contained within the CFS construct, which makes it even more difficult to identify commonalities among people with this diagnosis. For example, those who improve over time have significantly higher CFS symptoms during the first year of the illness (Friedberg, MacKenzie, Dechene, & Fontanetta, 1994). In another study, Hickie et al. (1995) found two subsets within their CFS samples: 73% consisted of a heterogeneous group with limited fatigue and neuropsychiatric symptoms and moderate disability; and 27% had clinical characteristics of somatoform disorders (i.e., overinclusive somatic and psychological symptoms, more illness behavior, and severe psychological morbidity). Even the construct of fatigue needs to be better differentiated into various dimensions (e.g., postexercise symptoms, flare-up symptoms, remission symptoms, allergy fatigue; Dechen, Friedberg, MacKenzie, & Fontanetta, 1994). Until more differentiated subgroups are developed, it will be exceedingly difficult to identify characteristics that are common for all people with the diagnosis of CFS.

The minor symptom criteria for CFS are primarily scored using binary classification (i.e., occurrence versus non-occurrence), and play a pivotal role in the assessment and diagnosis of this syndrome. Yet despite the importance of these symptoms in defining CFS, current approaches to charting and assessing symptoms rely on data collected at only one time point, and only the presence of symptoms is assessed (with exception of Jason, Holden, Taylor & Melrose, 1995; Jason, King, Tryon, et al., 1997; Jason & Taylor, 1994; Wood et al., 1994). Currently, there are no guidelines for physicians to follow when determining whether a symptom is severe enough to qualify as meeting the diagnostic criteria. If CFS is to be diagnosed reliably by health care professionals, cutoff points that determine when symptoms are not considered to be severe enough to meet the case definition for CFS may be needed to further standardize the diagnostic procedure. Without such standardization, samples of individuals diagnosed with CFS are likely to vary, not necessarily as a function of etiological factors alone but rather as a function of assessment procedures as well. Thus, the current U.S. case definition needs to be revised to clarify the significance of symptom severity in diagnostic and assessment procedures. 4/

In summary, progress has occurred with regard to the improved reliability and validity of CFS research. At the same time, problems remain which constitute important challenges for social science researchers. In the area of CFS epidemiology, critiques of sample selection biases in earlier studies (Richman, et al., 1994) have lead to more recent research that addresses the true prevalence of CFS in community samples that are not biased by help-seeking behaviors or access to the health care system (Jason, Taylor et al., 1995). However, a broadened interpretation of CFS might have complicated estimates of CFS prevalence by possibly confounding the diagnosis of CFS with diagnoses of other illnesses that have overlapping symptoms but that may not constitute CFS at all, or with conditions which are comorbid with CFS. Moreover, beyond the need to obtain accurate epidemiologic estimates of CFS prevalence for public health policy formulation, reliable and valid diagnoses are crucial for determinations of CFS treatment efficacy. We believe that it is crucial for CFS research to move beyond fuzzy recapitulations of the neurasthenia concept and clearly delineate precise criteria for diagnosing pure CFS and CFS that is comorbid with psychiatric disorders. It is also necessary to better differentiate CFS from other disorders which share some CFS symptoms but are not true CFS cases.


Editor's note. Samuel M.Turner served as action editor for this article.

Author's Note. Leonard A. Jason, Lynne Wagner, Renee Taylor, and Karen M. Jordan, Department of Psychology, DePaul University; Judith A. Richman, Department of Psychiatry, University of Illinois at Chicago; Fred Friedberg, Department of Psychiatry, State University of New York at Stony Brook.

Financial support for this study was provided by National Institue of Allergy and Infectious Disease Grant number AI36295.

We would like to express our appreciation to Fred Rademaker, Cheng Fang Huang, Bill McCready, Warren Tryon, Jackie Golding, David Lipkin, Morris Papernik, Andy Plioplys, Sigita Plioplys, Susan Rosenthal, Pat Fennel, Joyce Goodlatte, Jennifer Shlaes, Caroline King, Erin Frankenberry, Susan Torres, Dana Landis, Trina Haney Davis, Jennifer Camacho, Amy Kolak, Tanya Pernell, Dan Cantillon, and Barbara Smith for their constructive advice.

Correspondence concerning this article should be addressed to Leonard A. Jason, Department of Psychology, DePaul University, 2219 North Kenmore Avenue, Chicago, IL 60614.


1/ In comparing patients with chronic fatigue and depression, Komaroff et al. (1996) found high rates for sleep disturbance (98% vs. 95%), joint pain (73% vs. 50%), muscle pain (89% vs. 68%), and impairment in concentration (83% vs. 79%).

2/ If 73% of the patients were now within the normal range, it is surprising that only 60% indicated that they had "much or very much" improved and 60% continued to avoid exercise at least 50% of the time.

3/ In another important recent trial of cognitive-behaviour therapy, Deale, Chalder, Marks, and Wessely (1997) randomly assigned 60 CFS patients to 13 sessions of either cognitive-behaviour therapy or relaxation. At a final six-month follow-up, 70% of those completing cognitive-behaviour therapy achieved substantial improvement in physical functioning compared with 19% of those in the relaxation group (21% of patients who were offered an opportunity to participate in the study either refused or dropped out). A score of 4 on their fatigue questionnaire indicates excessive fatigue, and at the follow-up, those provided cognitive-behavior therapy had an average score of 4.1. Twenty-one of the 30 participants provided with cognitive-behavioral therapy were defined as a psychological case using the General Health Questionnaire (Goldberg, 1972) at pre-treatment (70%), but at follow-up, only 8 of 27 were defined as being a psychological case (30%). However, because 63% of patients who were free of psychiaric disroders achieved good outcomes, it is possible that cognitive-behavior therapy si also effective with patients without psychiatric disorders. A key issue for future research involves trying to determine those characteristics, whether they are high versus low symptoms or functioning, that best predict success with different types of interventions.

4/ There are also additional problems in this case definition. Individuals who did not have a new or definite onset of CFS are excluded. This is unfortunate, as a minority of patients have a lifetime prevalence. It might have been better to sub-classify patients on this dimension rather to exclude all those without a new or definite onset. It is also important to clarify exactly what a new or definite onset means. If a person was slowly getting sick over an eight-year period, from ages 27 to 35, would this case be included as a new onset? In addition, the definition stipulates that the fatigue is not substantially alleviated by rest. However, some patients report that if they engage in few activities, they can have minimal fatigue. It is only after engaging in some activities that overwhelming fatigue is experienced. The definition needs to be clarified to deal with these types of cases. In addition, the definition stipulates that the fatigue is not the result of ongoing exertion, however, as mentioned above, for some patients, it is only after mininal exertion that fatigue is experienced. Again, there is a need for better clarification of these issues. Finally, the new definition stipulates that the four or more minor symptoms must not predate the fatigue. It is unclear what predating the fatigue means. If a patient had only four minor symptoms, and one of the symptoms (sore throats) began five months before the overwhelming fatigue, the definition suggests that this individual would be excluded from a CFS diagnosis. Clearly, lack of precision in the definition will lead to problems in interrater reliability.

In addition, self-report data may lead to erroneous research results more often than previously thought. Self-report is unavoidable for some variables such as fatigue, which is a complex psychological state that cannot, as yet, be measured otherwise. This is clearly not the case for activity for which objective instrumented measurements are available and constitute the gold standard. Use of actigraphy measures in future studies might provide investigators with the ability to better measure and define CFS (Jason, King, Frankenberry, Jordan, & Tryon, 1997).



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