CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA

DIAGNOSTIC DILEMMAS, PART I

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CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA Dilemmas in Diagnosis and Clinical Management Mark A. Demitrack, MD

Chronic fatigue syndrome (CFS) and fibromyalgia have entered a resurgence of interest in the clinical and lay community in recent years. Formal descriptive definitions now exist in the peer-reviewed literature for both of these conditions.28,Io4 On the other hand, it is generally agreed that these conditions are not new, but have a rich historic ancestry.I9 An extensive medical literature documents the occurrence of illnesses marked by diffuse somatic symptoms without obvious physical cause. It was very early acknowledged that the onset and course of these conditions were closely associated with periods of physical and emotional stress. George Beard, the American neurologist who coined the term neurasthenia in the latter portion of the last century remarked, “Among the special exciting causes of neurasthenia may be mentioned the pressure of bereavement, business and family cares, parturition and abortion, sexual excesses, the abuse of stimulants and narcotics, and civilized starvation, such as is sometimes observed even among the wealthy order of society, and sudden These characteristics of the two illnesses, namely, retirement from bu~iness.”~ profound somatic distress in the absence of any grossly evident biological dysfunction, and their apparent close association with physical and emotional stressors has confounded the traditional, dualistic Western medical model in its attempt to conceptualize them. In a broad sense, these problems serve to frame the basic dilemma for these two conditions: What is their proper place in modern medical thought? Contemporary medical and psychiatric nosologies are most comfortable with unitary illness classifications that demand that an illness be seen fundamentally as either physical or psychological in nature. Unfortunately, clinical conditions, such as CFS and fibromyalgia, are neither. Simple in defini-

From Lilly Research Laboratories, Neuroscience Therapeutic Area, Indianapolis, Indiana

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tion, as illnesses, they are complex. In broad symptom profile, patients may be similarly grouped, nevertheless, medical issues and psychiatric conditions intertwine in a particular and complex fabric that is unique for each patient. An understanding of how these differing clinical vulnerabilities are formulated as a clinical illness must also be considered from the perspective of the evaluating clinician, who brings his or her own experience, opinions, and beliefs to bear on the problem (Fig. 1). This article discusses these dilemmas by examining several basic aspects of CFS and fibromyalgia. The author examines the current definitions for these two conditions and considers the areas of similarity in overall clinical presentation. Using the available data on neuroendocrine dysfunction in these conditions as an example, the author highlights some of the difficulties in determining the underlying pathophysiology, common or not, for these syndromes. The author concludes with an overview of principles for clinical management. In discussing these various points, the author hopes to convince readers that the currently articulated definitions of CFS and fibromyalgia serve an important clinical purpose, since they describe patients who exist in clinical practice, and whose accurate description is not established by any other clinical naming system. On the other hand, these definitions are clinically sterile, if not essentially useless, without a more comprehensive understanding of the multidimensional issues which may converge to produce the symptoms for a particular patient. In the

PSYCHIATRIC VULNERABILITIES

VULNERABILITIES

CLINICIAN EXPERIENCE, OPINIONS, AND BELIEFS

PATIENT EXPERIENCES, OPINIONS, AND BELIEFS

FORMULATION

Figure 1. The dilemma of chronic fatigue syndrome and fibromyalgia.

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end, a truly listening clinical ear combined with a nonjudgmental and pragmatically based treatment approach involving the collaborative efforts of patient and clinician may be expected to yield significant relief from these distressing syndromes. CASE DEFINITIONS AND CLINICAL DESCRIPTIVE ISSUES

In 1750, Sir Richard Manningham66provided one of the earliest known descriptions of a clinical illness substantially reminiscent of modern-day CFS, characterized by persistent fatigue and an accompaniment of vague and nonspecific somatic symptoms. He termed this illness, febricula or “little fever,” and wrote that the patients experience a profound ”listlessness, with great lassitude and weariness all over the body . . . [and] little flying pains.” Manningham noted a close association between this condition and periods of emotional stress. One of the more enduring terms used to describe this condition was offered by the American neurologist, George Beard. In 1869, he published a clinical report in the Boston Medical and Surgical Journal: describing the symptoms and treatment of neurasthenia, a name he chose from the Greek indicating his belief that the clinical features of the illness were a direct result of the loss of strength in nervous tissue. An extensive and informative literature of Beard’s writings on the topic survives, including his well-known 1880 text, A Practical Treatise on Nervous Exhaustion (Neurastkettia): Its Symptoms, Nature, Sequences, T~eatrnent.~ Neurasthenia as a diagnostic term has fallen out of the standard American nosologies, but it survives in the 10th edition of the International Classification of Diseases. Beard’s descriptions are remarkably observant, and though absent of the technical biological detail associated with contemporary studies of CFS, they are insightful in their appreciation of the clinical and diagnostic complexity surrounding this illness. Beard noted that ”the diagnosis . . . of neurasthenia is obtained partly by the positive symptoms and partly by exclusion . . . [it] may be associated with anemia and with almost every conceivable form of organic disease. . . . In such cases it is sometimes very difficult to ascertain whether it is the cause or the effect. The history of the symptoms will help us to decide this question.” This instruction remains a useful first principle guiding the clinical approach to CFS to the present day. The historic record leading to the modern concept of fibromyalgia has a similarly extensive history. Over 170 years ago, Balfour first remarked on the presence of “tender points” in individuals with rheumatic disease.*Valliex, in 1841, observed that in many instances the tender points could only be elicited upon palpation, the patient often being subjectively unaware of the specific anatomic presence of these locations at rest.97Gowers is credited, in 1904, with coining the term fibrositis in reference to this c o n d i t i ~ n Although .~~ he acknowledged the absence of gross evidence of inflammation, he felt confident that later research efforts would bear this pathophysiologic supposition out. The presence of clinically evident tender points are now considered a hallmark feature of the clinical condition known in contemporary terms as fibromyalgia. Despite this rich historic literature, and even though these clinical illnesses are known to occur commonly in clinical practice, until recently little effort was directed toward their formal, quantitative study. Contemporary interest was renewed by several investigations beginning in the early 1970s. In 1975, Moldofsky described the presence of an abnormality in deep, or nonrapid eye move-

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ment (non-REM) sleep in patients with fibromyalgia, the so-called alpha-intrusion pattern.hXAlthough the exact meaning of this observation remains an area of active research inquiry, this central nervous system finding provided a conceptual model which linked the clinical observation of poor sleep quality to an emerging view of the importance of central nervous system mechanisms involved in pain modulation in patients with fibromyalgia. Beginning with the report of a small case series by Tobi and colleagues in 1982,95and followed by the two larger series reported by Jones" and by Strauss6in 1985, a syndrome of profound fatigue appearing in the aftermath of a history of an acute infectious illness was described. Because these early reports highlighted the observation of subtle disruptions in cellular and humoral immunity in these patients, along with atypical patterns of serologic response to the Epstein-Barr and other viral antigens, an initial hypothesis proposed that this illness represented a state of chronic active infection with the Epstein-Barr virus. It is now well accepted that CFS is not an infectious disease. Indeed, chronic viral infection is not a tenable explanation for most, if not all, cases of CFS. On the other hand, a putative state of chronic immune activation remains a dominant theory of disease pathogenesis for this illness. A more complete discussion of this point is beyond the scope of this article, and the reader is referred elsewhere in this issue.9O As research efforts proceeded it became increasingly obvious that the inherently vague and nonspecific character of the symptoms with which patients presented, coupled with the very idiosyncratic and variable definitions employed in research studies, combined to make reasoned comparisons of the findings among different research reports virtually impossible. To address these concerns, substantive attempts have been made to achieve international consensus in the case definitions for these two illnesses. In April, 1987, the Centers for Disease Control and Prevention (CDCP) convened a working group with the express charge of establishing a consensus case definition for CFS.3yClinicians and researchers with varying scientific backgrounds and levels of clinical familiarity with the topic composed the consensus panel. Unanimous agreement was obtained in naming the newly operationalized syndrome, chronic fatigue syndrome, to highlight what was felt to be the most consistent and significant manifestation of the illness, and to avoid the use of etiologically-biased modifiers that were not applicable to all cases. Subsequent to the publication of this original definition, discussion appeared in the medical literature over several points. In particular, the initial published definition provided poor guidance on the nature of the overlap between chronic fatigue syndrome and psychiatric illness, especially depressive and anxiety disorders. I will comment further on these findings in the following section. Katon and R ~ s s additionally o~~ pointed out that the requirement, in the case definition, for a large number of unexplained medical symptoms further aggravated this situation because this merely seemed to bias for the selection of individuals at higher risk for concurrent psychiatric morbidity. In response to these criticisms, further consensus reviews of the definitions were convened.28,80As a result of these deliberations, more specific inclusion and exclusion criteria for psychiatric comorbidity have been proposed, while the required number of concurrent unexplained medical symptoms has been reduced to four. The most recent consensus panel has also attempted to harmonize the CDCP definition with some of the other key definitions in use in international settings.R'The specific criteria for this definition are outlined subsequently.

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International Consensus Definition of CFS Chronic Fatigue Syndrome

A) Clinically evaluated*, unexplained, persistent or relapsing chronic fatigue (> 6 months’ duration) that is of new or definite onset (has not been lifelong); is not the result of ongoing exertion; is not substantially alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social, or personal activities B) Four or more of the following symptoms are concurrently present for > 6 months: 1. 2. 3. 4. 5. 6. 7. 8.

Impaired memory or concentration Sore throat Tender cervical or axillary lymph nodes Muscle pain Multijoint pain New headaches Unrefreshing sleep Postexertion malaise

Idiopathic Chronic Fatigue Clinically evaluated, unexplained chronic fatigue (> 6 months duration), that fails to meet the definition for CFS *Recommended Clinical Evaluation Medical history and physical examination Mental status examination Laboratory screening battery to include: complete blood count with leukocyte differential, erythrocyte sedimentation rate, serum levels of alanine aminotransferase, total protein, albumin, globulin, alkaline phosphatase, calcium, phosphorus, glucose, blood urea nitrogen, electrolytes and creatinine, thyroid stimulating hormone, urinalysis Exclusionary Clinical Diagnoses Any active medical condition that could explain the chronic fatigue Any previously diagnosed medical condition whose resolution has not been documented beyond reasonable clinical doubt and whose continued activity may explain the chronic fatiguing illness Psychotic major depression; bipolar affective disorder; schizophrenia; delusional disorders; dementias; anorexia nervosa; bulimia nervosa Alcohol or other substance abuse within 2 years prior to the onset of the chronic fatigue and at any time afterward (From Fukuda K, Straus SE, Hickie I, et al: The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Intern Med 121:953-959, 1994; with permission.)

The development of an operational definition for fibromyalgia was similarly initiated from observational reports and then from formally convened consensus discussion by expert clinical panels. Compared with the methods employed for the case definition for CFS, a somewhat more rigorous attempt has been made to test the performance characteristics of the proposed definition in practice. In

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a detailed and controlled case discussion of 50 individuals with primary fibromyalgia (i.e., fibromyalgia occurring in the absence of known cause or evident contributory illnesses) matched with 50 healthy individuals, Yunuslo7emphasized the hallmark features of diffuse pain and the consistent presence of characteristic tender points on physical examination. Noted also in that report was the presence of a diverse array of minor features, including aggravation of symptoms by physical or emotional stress, poor sleep, fatigue, headache, irritable bowel symptoms, and numbness. In 1990, the American College of Rheumatology published the study report of a multicenter criteria committee directed to develop criteria for the classification of fibr~myalgia.'~~ Based on the systematic observation of 558 consecutive patients (293 with fibromyalgia and 265 controls), the definition outlined below was proposed. Performance properties of this definition showed a sensitivity of 88.4% and a specificity of 81.1% in the sample tested. Moreover, the absence of any substantial difference in the primary and secondary, or concomitant-disease subgroups on a number of clinical variables led this committee to suggest abandoning these distinctions at a diagnostic level. Importantly, there was an explicit recommendation to finally dispense with the older term, fibrositis, in favor of the more appropriately descriptive term, fibromyalgia.

American College of Rheumatology Criteria for the Definition of Fibromyalgia 1. History of widespread pain, defined as pain present in all of the following sites: left and right sides of the body, above and below the waist. Additionally, axial pain must be present. 2. The presence of pain in 11 of the following 18 bilateral tender point sites upon digital palpation (approximate force of 4 kg; must elicit the subjective sensation of pain from the subject; tenderness must be distinguished from pain): Occiput, at the suboccipital muscle insertions Low cervical, at the anterior aspects of the intertranverse spaces at C 5 C 7 Trapezius, at the midpoint of the upper border Supraspinatus, at origins, above the scapula spine near the medial border Second rib, at the second costochondral junctions, just lateral to the junctions on upper surfaces Lateral epicondyle, 2 cm distal to the epicondyles Gluteal, in upper outer quadrants of buttocks in anterior fold of muscle Greater trochanter, posterior to the trochanteric prominence Knee, at the medial fat pad proximal to the joint line (From Wolfe F, Smythe HA, Yunus MB, et al: The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Arthritis Rheum 33:160-172, 1990; with permission.)

Some aspects of these definitions merit highlight and discussion. Because there is currently no known biologic correlate which may serve as an external

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diagnostic validator of either illness, these diagnoses essentially remain diagnoses of exclusion. It is therefore crucially important to avoid premature closure with regard to alternative diagnoses, especially in the early stages of the illness. The importance of this issue is demonstrated in a recent report by Fitzcharles and c011eagues,2~which described a series of 11 patients referred for presumed or previously diagnosed fibromyalgia. All of these individuals on closer examination showed clear evidence of spondyloarthropathy that responded well to specific and aggressive treatment. In this report, and in many other clinical situations, the confusion arises because of the nonspecific nature of the fatigue or fibromyalgia symptoms, which may mimic the early stages of a vast array of illnesses which develop in an insidious fashion. It is, therefore crucial to continually review the available data to ensure that confidence in the accuracy of the diagnosis is optimized. Another important aspect of these definitions is that since no specific laboratory abnormality for either condition exists, detailed diagnostic evaluations beyond a basic laboratory workup, should be reserved for instances where the specific goal is to exclude an alternate, potentially explanatory condition. Finally, the choice of terms to name these conditions was, in both instances, intended to be a theoretically neutral one, highlighting the hallmark symptoms of these illnesses. The resulting definition is understood to capture a heterogeneous cluster of individuals rather than attempting to describe a single pathophysiologic entity. Research efforts may then elect to stratify the population on any of several potentially discriminating variables among the groups (i.e., sudden versus gradual onset of symptoms, family history, or concomitant personal history of psychiatric or medical disease). As may be expected, epidemiologic estimates of the prevalence of either of these conditions are confounded, to an extent, by the nonspecific nature of the definitions themselves and the lack of a validating laboratory test. Ample evidence supports the view that these conditions reside on the extreme end of a continuum of symptom severity in the general p o p ~ l a t i o nIn . ~ the ~ absence of a specific pathophysiologic correlate that may serve to define diseased from nondiseased individuals, the operational cutpoint to establish "caseness" is a somewhat arbitrary convention. Regardless of the definition employed, or the level of stringency for case definition, emerging data confirms the clinical suspicion that these illness are not uncommon in practice. Formal point prevalence estimates for CFS in primary care settings range as high as 3%?' Similar prevalence estimates have been reported for fibr0myalgia.3~In a typical tertiary care rheumatology practice, fibromyalgia patients often account for over 20% of the caseload, a number which is not dissimilar from the experience of the infectious disease practitioner in a tertiary care setting with respect to CFS.33In follow-up studies published to date, the long-term outcome of either condition is marked by chronicity, less than 10% of individuals on average returning to premorbid levels of f u n ~ t i o n i n gIdentified .~~ risk factors for a poor prognosis include the duration of the illness at time of presentation, the presence of a concurrent psychiatric disorder, and the fixed belief that the illness is due solely to a physical cause.15,46, 98, Io2 Indeed, the potential health care burden, clinical and economic, of these illnesses is not trivial. The article returns to these issues of prognosis and outcome in the later section on approaches to clinical management. Before leaving the topic of descriptive studies, a final point should be made about the overlap between chronic fatigue syndrome and fibromyalgia. The clinical boundary between these two conditions is sufficiently diffuse that many investigators have concluded that the definitions may merely be describing alternate sides of the same coin. For instance, it is recognized that symptoms,

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such as fatigue, sleep disturbance, headache, depression, anxiety, paresthesias, postexertional exacerbation of symptoms, and even an abrupt onset in the aftermath of a stressor, typical of CFS, are also commonly present in patients with fibromyalgia. Several groups have attempted to formally assess the relation between these two entities. Buchwald and colleagues7provided a detailed clinical and laboratory report on a series of 50 patients (46 women, four men) with primary fibromyalgia. She detailed, in fibromyalgia patients, the presence of symptoms characteristic of what was then referred to as the “chronic active Epstein-Barr virus infection syndrome.” Of note, she drew attention to the high prevalence of symptoms not previously thought to be characteristic of fibromyalgia, namely, recurrent sore throat (54% of subjects), recurrent rashes (47%),a history of allergies (64%), chronic cough (40%), recurrent adenopathy (33%), and recurrent low-grade fevers (28%).In 55% of their sample, the onset of illness was abrupt, in the aftermath of what appeared to the patient as an acute viral syndrome. Similarly, Goldenberg and described the history and physical examination (including tender points) of a series of 27 patients with debilitating fatigue of greater than 6 months duration. Seventy percent of the sample of chronically fatigued subjects described the presence of diffuse musculoskeletal pain. In this group of chronic fatigue patients, the tender point score was indistinguishable from the score in a concurrent group of patients with fibromyalgia. They went on to note that, in their experience, more than 90% of patients with chronic fatigue report persistent musculoskeletal pain, hence the chronic fatigue sample described in their report ”may underrepresent the association of fibromyalgia with chronic fatigue syndrome.” Finally, the importance of the association between these clinical entities has also been highlighted by the recommendation of the 1991 joint National Institute of Mental Health/National Institute of Allergy and Infectious Diseases (NIMH/NIAID) workshop,8O which recommended a tender point examination as part of the overall clinical assessment of CFS. The specific relation between fibromyalgia and CFS remains, however, unclear. Further descriptive studies in which patient subsets presenting with varying features of these operational syndromes are compared, cross-sectionally and when followed over time, would be of great help in clarifying some of these issues. In the following section, the author briefly discusses alternative approaches that may shed light on this dilemma by comparing these syndromes at a biologic level.

THEORIES OF PATHOGENESIS: STUDIES OF NEUROENDOCRINE FUNCTION IN CFS AND FIBROMYALGIA

Several, sometimes apparently conflicting, theories have been advanced to explain the pathophysiology of CFS and fibromyalgia. Arguably, the debate is more polarized and lively in the area of CFS. In that condition, the early focus on the postinfectious onset of some patients has led to a substantial preoccupation of the research literature with the functional integrity of the host immune response.9oBecause of the reminiscence between the symptoms of CFS and those of an acute infectious illness (i.e., fatigue, feverishness, myalgias, athralgias, adenopathy, sore throat, sleep disturbance), great effort has been directed at detecting immunologic evidence which would support the view that a fundamental pathophysiologic underpinning of the disease is a state of chronic immune activation. Some intriguing evidence of cytokine dysregulation and alteration in phenotypic surface markers on peripheral lymphocytes lends credence

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to this viewpoint.* On the other hand, there is ample published data that refutes this model. For instance, the immune disturbances that have been described are modest in magnitude:* only variably present:* bear no apparent relation to disease severity or phenotype?l and are not at all specific for CFS.27,29, 43, 64, 65 Moreover, there is no convincing evidence that, even when present, these markers are of any meaning diagnostically or prognostically.3°,37, 72 In a similar manner, for fibromyalgia, the initial observations of disturbances in the functional regulation of slow-wave sleep have served to focus the field of study. These findings early led researchers to consider central nervous system integrative functions as key to understanding the development of fibromyalgia. Additional lines of research have emphasize fibromyalgia as a disorder of pain regulation. Intriguing reports of disruptions in the central regulation of substance Pn have lent support to this model. Nevertheless, these findings are also plagued by the same concerns that were previously mentioned for CFS: these disease correlates are not always demonstrable in replication studies, they do not appear specific or unique to fibromyalgia, nor do they bear a clear relationship to disease severity or clinical course. Interposed in the midst of the biologic explanations of both of these illnesses has been the contentious, yet well-replicated, observation of a complex relationship between these clinical conditions and psychiatric illness. In the current literature on CFS and fibromyalgia, it did not take long for investigators to appreciate the enormity of this issue. For example, depressed mood has been noted in most patients in most case series of CFS?8,54,55,67,99 Similar observations have been reported for patients with fibromyalgia.’,13, 31, 42, 51, 71, lo3 Obviously, given the fact that major psychiatric illnesses such as major depression or the anxiety disorders may be lethal if left untreated, identification and aggressive treatment of psychiatric illness, when present, is a pressing clinical need. It is unfortunately true, though, that in most cases the clear differentiation between a depressive or anxiety disorder and CFS as separate and distinct clinical conditions based on descriptive historical information alone is simply not possible. The obvious difficulty of this clinical problem was recognized nearly instantly after the publication of the original CDC case definition. An even more malignant problem than the confusion surrounding differential diagnosis is the frequently held view that psychiatric symptoms are, in a sense “red herrings.” Proponents of this view suggest that the depressive and anxiety symptoms evident in some patients with CFS or fibromyalgia are most parsimoniously understood as a psychologic reaction to the debility of the fatigue or pain syndrome itself, and hence require no specific or aggressive treatment, but can be expected to resolve once the primary condition (i.e., the chronic fatigue or fibromyalgia) is treated. This perception is simply not supported by the available data. To use CFS as a specific example, studies have approached this issue by examining rates of psychiatric illness in patients with chronic fatigue syndrome compared to other debilitating medical illnesses. Examples of these other illnesses include neuromuscular disease,’9 rheumatoid and multiple sclerosis.” In general, these studies are most consistent with the view that the burden of psychiatric illness is greater in patients with CFS than in comparably disabled medically ill patients. It is also true, though, that although this observation of high lifetime psychiatric morbidity is important, equally notable is that in almost all studies, at least 25% of subjects with chronic fatigue syndrome or fibromyalgia show no evidence, either past or *References 8, 10-12, 23, 36, 41, 50, 52, 56, 59, 61, 62, 86, 89, 96.

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current, for formally diagnosable psychiatric illness. Considered in aggregate, it appears safe to say that the relationship between psychiatric illness and these two puzzling somatic conditions is complex and interactive, and is unlikely to be reduced to a simple either/or relationship in most cases. I believe that the available clinical descriptive data argues in a compelling fashion for two conclusions. First, the current definitions of major psychiatric illness on the one hand and chronic fatigue syndrome or fibromyalgia on the other demarcate, at best, overlapping, but not identical phenomenologic domains. Second, the frequent co-occurrence of depressive or anxiety symptoms with these two latter illnesses cannot be explained away simply as a reaction to the degree of functional disability imposed by the chronic illness itself, and represent bona fide medical issues in their own right. It was precisely these observations of a complex relationship with psychiatric illness that initially led me and my colleagues to pursue research into neuroendocrine function in patients with chronic fatigue syndrome and fibromyalgia. As a starting point, we began by focusing on the clinical observation that in both of these conditions, the onset and course of symptoms appeared to be exacerbated by periods of physical and emotional stress. Given that the effects of these stressors are mediated via the coordinated activation of the hypothalamic-pituitary-adrenal (HPA) axis, we proposed that the phenomenologic overlap between CFS, fibromyalgia, and a variety of primary psychiatric illnesses may reflect the involvement of a shared biologic pathway (i.e., the HPA) that may be variously dysregulated by a disparate variety of infectious or noninfectious antecedent events. Considered from this perspective, several additional issues suggested to us that a focus on the HPA axis may be a particularly useful domain of study and may help in establishing a more integrative view of the pathophysiology of these syndromes. A first point was the well-established observation that a specific type of depressive patient, namely those with melancholia, demonstrate a characteristic disruption of the normal diurnal rhythmicity of the pituitary-adrenal axis?, 78 This disturbance involves an elevation of adrenal glucocorticoid output, usually seen as an earlier onset of the morning surge of the axis, in conjunction with enhanced cortisol secretion in the late afternoon. Over the past decade, detailed studies of the HPA axis in melancholic depression have led to the development of a model of neuroendocrine dysregulation, which suggests an excessive central release of the hypothalamic secretogogue, corticotropin-releasing hormone (CRH), as a key pathophysiologic event accounting for the glucocorticoid excess. In parallel with this work, it has become increasingly apparent that the melancholic subtype represents only one, severer, variant of the illnesses subsumed under the label major depression. Interestingly, several other forms of depressive illness have been studied that lack the features characteristic of the more classic melancholic depression. These depressive subtypes are of particular note because of their overlap with the symptoms of fibromyalgia and CFS (i.e., profound fatigue, prominent somatic distress, and mood reactivity). Forms of these more “anergic” depressive syndromes include the depressive phase of manic-depressive illness, seasonal affective disorders (SAD), the so-called atypical major depression, and the depressive syndromes seen in the context of certain endocrinopathies such as primary hypothyroidism and the postoperative state of Cushing’s disease. Most intriguing is that several reports of these conditions suggest a pattern of HPA function in these syndromes reflecting inappropriately normal or reduced activation of the HPA axis, which itself appears mediated by a reduction in central nervous system input to the 49, 53,75, 76 This latter observation has interested several research groups because it

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is known that the central biochemical driver of HPA tone, CRH, is itself a behaviorally active peptide, whose central administration in animals produces a state of physiologic and behavioral arousal.16,92, 93 It has been speculated that, in humans, reduction in central nervous system availability of CRH could contribute to the clinical features of these conditions. It was intriguing to our group that one could also wonder whether a deficiency of glucocorticoids could contribute to the observed symptoms of these "atypical" depressive syndromes, and to the features of CFS and fibromyalgia. Indeed, one could argue that a compelling clinical symptom similarity exists between patients with these latter illnesses and patients with known glucocorticoid deficiency. Shared features include debilitating fatigue, an abrupt onset precipitated by a stressor, arthralgias, myalgias, feverishness, adenopathy, postexertional fatigue, exacerbation of allergic responses, and gross disturbances in mood and sleep. Even more intriguing is the possibility that we may begin to propose an integrative conceptual model, which proposed that some of the immunologic disturbances in patients with CFS and fibromyalgia noted above may be seen as a logical functional consequence of a glucocorticoid deficient state, since glucocorticoids represent the most potent endogenous immunosuppressive compounds. Circumstantial support for the view that physiologic derangements in glucocorticoid tone may alter immune function are suggested by animal studies which have shown that a defect in the responsiveness of the HPA axis to immune mediators confers a risk for the development of inflammatory disease.", 85 Further evidence in humans demonstrates that withdrawal from hypercortisolemic states has been associated with the exacerbation of autoimmune thyroiditi~?~ as well as the development of myalgias, arthralgias, muscle weakness,z2and even severe fibromyalgia.21 The principle results of our work to date16,18are summarized in Table 1. Consistent with the ideas suggested in the preceding paragraphs, the data from our studies support the view that a common finding in patients with CFS and fibromyalgia is a reduction in basal glucocorticoid tone. It is also of interest that there are preliminary indications of subtle divergences of functional organization Table 1. SUMMARY A N D COMPARISON OF NEUROENDOCRINE ABNORMALITIES IN CHRONIC FATIGUE SYNDROME AND FIBROMYALGIA Fibromyalgia Brain

Adrenal

Chronic Fatigue Syndrome

Insulin tolerance testing CSF CRH, ACTH

Impaired

Normal

-

Reduced

Basal PM ACTH Basal AM ACTH oCRH PM challenge

Normal Exaggerated Exaggerated ACTH

Blunted? Blunted Blunted ACTH

Basal PM cortisol 24-Hour UFC ACTH challenge oCRH PM challenge

Elevated Reduced

Reduced Reduced sensitivity, J, capacity Normal cortisol

-

Reduced cortisol

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at the hypothalamic-pituitary level between these conditions. Whether these findings are real and reflect true disease differences, or reflect the dynamic evolution of a common underlying pathophysiologic process, is an active focus of our group's research efforts at this time. Other groups have provided corroboration of these results,5. 14, 35, Io6 though some have As might be expected given the information discussed in this chapter, yet another set of dilemmas emerges for an understanding of CFS and fibromyalgia which results in the advice of caution when attempting a more thoughtful interpretation of these findings. These caveats are important to keep in mind when the reader is considering any published reports on these illnesses. Most important, it remains to be seen that the populations we have studied are truly representative of the wider universe of patients with chronic fatigue or fibromyalgia. Indeed, in the fatigue patient subset, we examined an unusually chronic set of patients (on average > 6 years of persistent symptoms), with a rather diverse psychiatric history. Alternatively, the fibromyalgia patient group reported by Crofford16 consisted largely of a non-psychiatrically ill patient cohort. The results of these specific selection factors may substantially restrict the generalizability of the results. Another consideration is in fully appreciating cause and effect. In a recent report by Leese and colleagues from Great they showed that healthy individuals, when studied under conditions of altering work schedules of day shift to night shift, displayed a pattern of HPA axis dysfunction resembling that seen in our patients with chronic fatigue syndrome.18 On the other hand, if the defect we have described is not a primary event, but reflects an acquired disruption of the altered sleep-wake cycles of the illness itself, symptomatic effects of such circadian desynchrony may still occur. In fact, this finding may provide a compelling paradigm to explain the efficacy of some of the demonstrably useful clinical interventions (i.e., exercise, cognitivebehavioral therapy), which is discussed in the final section. ISSUES IN THE THERAPEUTICS OF CFS AND FIBROMYALGIA A Pragmatic Approach to Clinical Management

As might be expected from the material the author has presented to date, treatment approaches based on a unitary disease model have not yielded particularly encouraging results. For instance, a randomized, double-blind, placebocontrolled trial of the antiviral agent acyclovir in chronic fatigue syndrome, based on the causal assumption of a chronic active Epstein-Barr viral infection was unequivocally negative.87Other immune-specific approaches have also resulted in similarly disappointing results.", 63, 74 An outcome of this work has been a gradual evolution towards the formulation of a multidimensional model of how illnesses such as chronic fatigue syndrome and fibromyalgia develop. A representation of some the factors included in such a model is listed below, and may be useful as starting point in discussing a clinical approach to these conditions. A Multidimensional Perspective on the Vulnerabilities for the Development and Persistence of CFS and Fibromyalgia Predisposing Factors Stressful life events (acute or chronic) Psychiatric illness Personality factors (somatization) Constitutional factors (chronic medical illness, history of atopy or allergies)

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Precipitating Factors Severe infectious illness Physical trauma (surgery, accidental trauma) Severe emotional stressors Perpetuating Factors Untreated psychiatric illness Ongoing, unaddressed psychosocial stressors Unrecognized medical illness Disruptions in rest-activity cycle, particularly with avoidance of physical activity Abnormal illness attributions ( e g , the fixed belief in an ongoing infectious cause unsupported by empirical evidence) Prolonged time away from work For instance, it is in fact, relatively unusual for chronic fatigue syndrome or fibromyalgia to occur de nova." In a majority of cases, careful historical query will reveal a number of factors, such as prior psychiatric illness or a history of allergy or atopy which are believed to increase an individual's vulnerable risk for the development of these syndromes. Hence, certain factors may be considered as "predisposing events." To the extent that they remain untreated, at the very least they impede the ability to make an accurate clinical diagnosis. In many instances, a specific "precipitating factor" can also be isolated. Though these events are rarely etiologically related to the illness, they are nonetheless important as organizing historical anchor points, at least from the perception of the patient, and as such can assist the clinician in understanding the nature of the illness from the viewpoint of the patient. It is worth noting that, despite strongly held beliefs to the contrary, there is good evidence to demonstrate that common viral infections are not associated with an increased risk for the development of chronic fatigue syndrome,")" though, in a small percentage of patients with severe viral infections, a persistent fatigue syndrome may clearly emerge.40,lol What is most notable is that the types of reported precipitants are quite diverseY9 and may even be spread out over an interval of time (i.e., chronic psychosocial stress). Probably of most immediate relevance to treatment planning for patients with chronic fatigue syndrome and fibromyalgia are the elements which are listed under the heading of "perpetuating factors." It is an unfortunate fact that, by the time the patient has arrived for clinical assessment, the symptoms may have persisted for many months, if not years. Confusion or controversy over the diagnosis with previous clinicians, resulting an incomplete medical and psychiatric assessment, unaddressed concurrent medical or psychiatric illness, profound disruptions in sleep-wake cycles, prolonged time away from work or significantly reduced work productivity and emerging psychosocia1 distress are often present, and therefore become the starting point for the formulation of diagnosis and the implementation of a clinical treatment plan. In the absence of more complete knowledge about the origin of CFS and fibromyalgia, the considerations outlined above have inclined most experts towards a more pragmatically-based, multidimensional approach to clinical management of these conditions. Indeed, this model leads logically to treatment approaches which are fundamentally rehabilitative in character, directed more towards identification of target areas of symptomatic distress with the development of a treatment plan composed of an eclectic blend of therapeutic options and with clear specification of measurable outcomes. Such a framework is outlined subsequently.

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A Framework for the Pragmatic Clinical Management of CFS and Fibromyalgia Initial Evaluation A collaborative approach is desirable Medical planning Psychiatric planning Optimize confidence in the clinical diagnosis Thorough review of available clinical records Medical history and physical examination Psychiatry history and mental status examination Medication review (including alternative or nonprescription therapies) Minimize laboratory evaluation Basic recommended screening labs (per CDC definition) Other investigations only to confirm alternative diagnoses Obtain supplementary information Work history Social and family history Ask for the patient’s appraisal and understanding of the illness What caused it? What are the major sources of symptomatic distress? What helps it? What questions would the patient like to have answered? Treatment Planning Pharmacologic treatment Antidepressants Nonsteroidal anti-inflammatory agents Other drug therapy in a specific symptom-directed manner Avoid polypharmacy Nonpharmacologic treatment Sleep habit normalization Physical activity review and reintroduction Cognitive-behavioral or other psychotherapies as indicated Alternative therapies Review any use of these interventions and assess outcome with patient Outcome Assessment Follow a broad-based functional outcome assessment, based on agreed treatment targets Fatigue (duration, severity, exacerbating factors) Pain management (location, duration, severity, exacerbating factors) Psychosocial adjustment (employment, family, leisure, and social function) Sleep pattern Activity pattern Critically evaluate new or unusual symptoms Avoid premature diagnostic closure, but be cautious with overinvestigation

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During the initial evaluation, a primary goal should be directed at clarifying the nature of the patient’s most distressing current symptoms, comprehensively reviewing existing medical and laboratory records, and obtaining supplementary information from family or friends. Efforts directed at optimizing one’s confidence in the appropriateness of assigning the clinical diagnosis of CFS or fibromyalgia from the start cannot be overemphasized. Because of the complex array of somatic and behavioral symptoms which are frequently present, it is often extremely useful to perform this evaluation as a collaborative endeavor between an internist and a psychiatrist. Laboratory evaluation is employed as an initial screening assessment; further investigation is to be discouraged unless clearly indicated to rule out a suspected alternative disease. As alluded to earlier, in many instances, a clear delineation between either of these syndromes and an accompanying medical or psychiatric disease, which is not completely remitted, may simply not be possible. Because of this, it is crucial at this point to determine the patient’s view of how the illness has developed, and in what manner they view the factors which have contributed to and are perpetuating their distress. In the most optimistic scenario, both patient and clinician can agree on the specific target symptoms that form the illness in question, and then discuss in a nonjudgmental manner the domains of both somatic and psychologic distress. It is more important to assure that key clinical target symptoms are being appropriately identified and aggressively addressed (i.e., treating depressive and anxiety symptoms or ensuring that a confounding medical condition is well-managed) than to engage in an adversarial debate over where the chronic fatigue or fibromyalgia ends and the other illness begins. A practical, collaborative approach to symptom identification and treatment planning is essential. Once the clinical diagnosis is established with confidence, and specific targets for clinical intervention are identified, the patient and clinician can begin the process of treatment planning. Options for clinical management may be grouped broadly into nonpharmacologic or pharmacologic interventions. I will consider the former options to begin with. As a first step, a review of the patient’s sleep history is critical. A diarybased approach may sometimes be useful in clearly documenting sleep patterns. Sleep is rarely normal in this patient population. Early in the course of the illness, increasing amounts of sleep may appear restorative or at least provide brief respites from conscious awareness of the individual’s distress. The usefulness of these strategies is, however, rapidly exhausted. What may eventually emerge is a pattern of gross sleep fragmentation with extended periods of daytime napping. At this point, the quality of sleep is generally poor and may have itself become a perpetuating factor in the current distress of the illness. Indeed, it has even been suggested in laboratory settings that chronic sleep interruption may induce a clinical symptom pattern resembling fibromyalgia in otherwise healthy individuals. As mentioned in the previous section, in healthy individuals sleep phase shifting may result in pattern of HPA dysfunction similar to that seen in patients with CFS57;the functional consequences of this physiologic change are not known. A plan for renormalization of sleep scheduling should be introduced gradually, changing basic patterns abruptly is rarely possible and, hence, is countertherapeutic. A formal sleep evaluation with nocturnal polysomnography may also be indicated if specific symptoms such as abnormal nocturnal movements or snoring suggest the presence of a primary dyssomnia. Another important domain of inquiry for treatment planning concerns physical activity. Almost by definition, there is a profound reduction in the amount

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of time spent in routine and leisure activity compared to premorbid levels of function. The consequences of this degree of sedentary activity pattern are physiologically and behaviorally diverse, potentially affecting sleep quality, mood, general sense of well-being, cardiovascular fitness, as well as increasing the likelihood of physical injury if activity is resumed at high levels abruptly. It is this latter issue that often serves as the greatest hurdle for resumption of physical activity; upon resumption of activity, the patient may overestimate their current tolerance level. The result is increased pain and fatigue, which may be inaccurately appraised as an indication that resumption of any physical activity will not be tolerated, leading to an unproductive and self-reinforcing cycle of continued physical inactivity. There is no evidence to support the view that ”aggressive rest” is an appropriate treatment for CFS or fibromyalgia. In fact, accumulating data from controlled clinical trials supports the view that resumption of physical activity is a fundamental building block for a comprehensive rehabilitation strategy for these illnesses.26As with the recommendations for sleep change, resumption of physical activity should ideally occur in a graded fashion, at an intensity level and rate tailored to the patient’s level of functional impairment. A consultation from a physical medicine clinician may be of use in the initial stages of implementation. A final area of nonpharmacologic intervention is psychotherapy. Psychotherapy is not indicated in all patients with CFS or fibromyalgia. When it is considered, though, there are, of course, many different varieties of psychotherapeutic technique from which to choose. Unfortunately, few have received formal study in CFS and fibromyalgia. When identifiable psychiatric illness or psychosocial distress is present, the decision to include an individual, family or couples-based treatment should be based on traditional factors such as patient and clinician preferences or availability. Of more specific interest is recent work which has explored the particular utility of cognitive-behavioral psychotherapeutic treatments in these conditions. Several controlled clinical trials have now been completed, and the aggregate data is extremely encouraging to suggest that this approach may hold great promise for producing a sustained improvement in functional 83 In these approaches, an emphasis is placed on understanding the patient’s appraisal of the nature and cause of their functional limitations, assembling empirical data to support or refute specific illness beliefs. Part of the rationale for employing this treatment approach has grown from observations of risk factors associated with disease persistence in follow-up studies. For example, in that work, it has repeatedly been shown that the fixed belief in an external cause for the patient’s symptoms (i.e., belief that the illness is due to a virus or to some irreversible brain disease) is one of the best predictors of disease persistence over time.82Conversely, patients who view the disease from a more broad-based perspective, acknowledging that a combination of internal (psychologic)and external (physiologic)factors may have contributed to the illness, in general have a much more favorable prognosis. This has led some researchers to speculate that these illness beliefs may, therefore, have a profound influence on the choice of coping strategies and treatment options, and, as a result, influence the outcome of the illness over time. An example of the applicability of this approach can be seen with regard to the frequently held patient belief that physical activity is harmful and should, therefore, be avoided. As was discussed in the preceding paragraph, the overwhelming body of clinical data is at odds with this view. A focus of a cognitive-behavioral therapy would be directed at evaluating the validity of this belief with the patient, with the goal of gradual reintroduction of physical activity. Unfortunately, there is no convincing evidence to suggest that any specific

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pharmacotherapeutic agent is uniquely effective in the treatment of CFS or fibromyalgia, though numerous agents of widely varying mechanism have now been studied.2uIndeed, if the illness paradigm proposed in this article is correct (i.e., the illness represents a multifactorial disease process), then these results should not be entirely surprising. At the present time, pharmacotherapy plays an important role when employed in a symptom-specific manner as an adjunct to a comprehensive plan of clinical management for these illnesses. The most reliable data exists for the use of nonsteroidal antiinflammatory medications and for antidepressants.2uSome basic principles should be observed when employing these agents. First and foremost, the clinician should be aware of why the medication is being prescribed in the first place: what is the specific symptom that the medication is intended to relieve. Keeping this in mind will greatly assist in assessing efficacy of the intervention. A second principle is based on the common observation that patients may often be idiosyncratically sensitive to routine starting doses of these medications; this is particularly true for the antidepressants. Hence, it is often useful to start at a dose one-half or less of the usual starting dose. On the other hand, there is no evidence that routinely lower doses are optimal for this patient group, therefore, in all instance, full therapeutic doses of the medication should be pursued prior to assessing true efficacy. Finally, given the symptom complexity of these conditions, and because their course of recovery is slow, modifications in treatment regimen should be made slowly, and only after sustained periods of observation for clinical effect. Cessation and reintroduction of a medication may clarify ambiguous responses. If at all possible, polypharmacy should be avoided. Although an extended discussion of this topic is beyond the scope of this article, a final mention should be made of the use of nontraditional or complementary medical approaches. Given the fact that these conditions remain poorly understood, and patients are often faced with frank rejection and a disparaging view from traditional medical practitioners, it is not surprising that patients with CFS and fibromyalgia are among the high utilizers of alternative medical therapies.", 69 It is important that use of these therapeutic approaches be included in the history obtained from the patient. In some instance, these interventions can be of great help for the patient; hence, it is critical that the clinician is aware of their use. This allows interventions to be coordinated, so appropriate evaluation of the effect of any intervention, traditional or not, can be clearly evaluated. In addition, many nontraditional medications may have important drug-drug interaction consequences. It may therefore be helpful to ask the patient to bring in the specific medications they have been prescribed, or to speak with the alternative medicine provider directly. CONCLUSION

CFS and fibromyalgia are two common and disabling clinical conditions that frame one of the enduring dilemmas of Western medical thought: they reside confidently in the vague boundary between mind and body. A full appreciation of these conditions requires a careful and inquisitive clinical stance that brings together the multiple threads leading to the patient's current symptomatic distress. Breadth of scope in clinical assessment and pragmatism in treatment planning are essential elements of a successful approach to these conditions. Though rarely life threatening, for the sufferer, the occurrence of these illnesses can be life transforming. Recent advances in clinical definitions and

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descriptive research have helped to validate some of the insights obtained in anecdotal fashion from the historical literature. Although much remains to be understood, particularly in elucidating the core pathophysiologic underpinnings of these conditions, an informed and compassionate approach to treatment may, nevertheless, yield significant symptomatic relief.

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Address reprint requests to Mark A. Demitrack, MD Senior Clinical Research Physician Lilly Research Laboratories, DC 0532 Lilly Corporate Center Indianapolis, IN 46285