4
IOM Review: Difficult-to-Diagnose and Ill-Defined Conditions*

The committee reviewed information on the development of screening instruments in order to contribute to the understanding and assessment of the adequacy of the CCEP protocol. The role of screening in the area of ill-defined conditions is to be able to identify a subset of individuals from a larger group who clearly fit a description of interest. Screening is not synonymous with diagnosis. Therefore, the criteria for a good screening instrument are not the same as the criteria for diagnosis.

Screening includes the systematic collection of information. It differs from a survey in that the goal of a survey is to make inferences, whereas the goal of a screening instrument is to identify a particular group of people. It is also important to note that screening does not take place under static conditions. Over time, progress made in the understanding of these conditions will necessitate different generations of the screening instrument. This does not imply that the first instrument developed is bad, but rather that time leads to new knowledge, which leads to the ability to improve the instrument.

A screening instrument should be systematic, quantitative, standardized, and contain tests and procedures which the population to be screened is willing to undergo. The procedures should be specified in advance, one should be able to assign numerical values to nonnumerical characteristics (e.g., the severity of

*  

The material in this section is based, in part, upon presentations and discussion by Dedra S. Buchwald, M.D., Daniel Clauw, M.D., Lt. Col. Tim Cooper, M.D., Nelson Gantz, M.D., Penelope Keyl, M.D., Howard Kipen, M.D., Robert Simms, M.D., and Frederick Wolfe, M.D.



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--> 4 IOM Review: Difficult-to-Diagnose and Ill-Defined Conditions* The committee reviewed information on the development of screening instruments in order to contribute to the understanding and assessment of the adequacy of the CCEP protocol. The role of screening in the area of ill-defined conditions is to be able to identify a subset of individuals from a larger group who clearly fit a description of interest. Screening is not synonymous with diagnosis. Therefore, the criteria for a good screening instrument are not the same as the criteria for diagnosis. Screening includes the systematic collection of information. It differs from a survey in that the goal of a survey is to make inferences, whereas the goal of a screening instrument is to identify a particular group of people. It is also important to note that screening does not take place under static conditions. Over time, progress made in the understanding of these conditions will necessitate different generations of the screening instrument. This does not imply that the first instrument developed is bad, but rather that time leads to new knowledge, which leads to the ability to improve the instrument. A screening instrument should be systematic, quantitative, standardized, and contain tests and procedures which the population to be screened is willing to undergo. The procedures should be specified in advance, one should be able to assign numerical values to nonnumerical characteristics (e.g., the severity of *   The material in this section is based, in part, upon presentations and discussion by Dedra S. Buchwald, M.D., Daniel Clauw, M.D., Lt. Col. Tim Cooper, M.D., Nelson Gantz, M.D., Penelope Keyl, M.D., Howard Kipen, M.D., Robert Simms, M.D., and Frederick Wolfe, M.D.

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--> symptoms), and there must be standardized questions and responses. In addition, a good screening instrument does not just ask about the presence or absence of symptoms, it also asks about the presentation of the symptoms; under what circumstances they occur; and their intensity, severity, frequency, and duration (how long before a symptom resolves as well as how long the patient has been experiencing it). With the development of a good screening instrument, one can elicit important information that will help identify a group of patients about whom one wishes to answer further questions regarding diagnosis and treatment. CHRONIC FATIGUE SYNDROME Chronic fatigue syndrome is a clinically defined condition characterized by severe, disabling fatigue that persists for at least 6 months and has a definite onset. The symptoms include self-reported problems in concentration, short-term memory, sleep disturbances, and musculoskeletal pain. A diagnosis is made only after alternative medical and psychiatric causes of fatiguing illness are excluded. There are no diagnostic tests that can validate its diagnosis, no pathognomic medical characteristic that is common to all patients, and no defined treatment that alleviates the symptoms for all patients. A major question surrounding diagnosis of CFS concerns whether CFS or any of its subset is a pathologically discrete entity as opposed to a debilitating but nonspecific condition shared by many different entities. In 1994, the CDC convened the International Chronic Fatigue Syndrome Study Group to develop a conceptual framework and a set of research guidelines for use in studies of CFS. This group developed the following criteria for defining chronic fatigue syndrome (Fukuda et al., 1994). A person can be classified as having chronic fatigue syndrome if both of the following criteria are met: clinically evaluated, unexplained, persistent, or relapsing fatigue of new or definite onset that is not due to ongoing exertion, is not substantially relieved by rest, and results in a substantial reduction in previous levels of occupational, educational, social, or personal activities; and the concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred for at least six months: impaired short-term memory or concentration severe enough to cause substantial reduction in previous levels of activity; sore throat; tender cervical or axillary lymph nodes; muscle pain, multijoint pain without joint swelling or redness;

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--> headaches of a new type or severity; unrefreshing sleep; postexertional malaise lasting more than 24 hours. The minimum laboratory evaluation of patients with suspected CFS includes complete blood count with differential; electrolytes, BUN (blood urea nitrogen), creatinine, calcium, glucose, and thyroid function tests; erythrocyte sedimentation rate; antinuclear antibodies; and urinalysis. Although many patients have significant abnormalities on routine lab tests, uniformity of abnormalities is lacking, and therefore routine laboratory tests cannot be used to determine whether a patient has CFS. No single cause of CFS has been identified. Of the patients diagnosed with CFS, 80% or more reported that it started with a viral illness. Many suspected agents were reviewed including the Epstein-Barr virus, but none have been found to be causative for CFS. From 60% to 70% of CFS patients reported allergies, compared to 20% of the general population. A variety of tests indicated that there does seem to be heightened reactivity to allergens and a higher prevalence of allergies in patients with chronic fatigue syndrome. Since allergies are immunologic phenomena, scientists started investigating other potential immunological problems. Findings included decreased natural killer cell number and activity, altered lymphocyte subset numbers and percentage; and increased expression of activation markers on lymphocyte subsets. However, none of these findings was ultimately found to be adequately consistent to be used as a diagnostic measure. Other areas investigated included neuroendocrine and metabolic abnormalities. Although abnormalities do exist in some patients with CFS, there is disagreement over their relevance. A recent theory is one of dysfunction of the autonomic nervous system. Some of the symptoms of chronic fatigue syndrome can mimic conditions associated with autonomic dysfunction, for example, neurally mediated hypotension. This is a condition in which the general symptoms include lightheadedness, sweating, abdominal discomfort, blurred vision, and then presyncope and fainting. The Tilt Table test is used to diagnose neurally mediated hypotension. When Tilt Table testing was applied in a study by Bou-Holaigah et al. (1995), an abnormal response to upright tilt (i.e., development of syncope or severe presyncope with at least a 25 mm Hg decrease in systolic blood pressure and no associated increase in heart rate) was observed in 22 of 23 patients with CFS versus 4 of 14 controls. The authors of the study concluded that CFS is associated with neurally mediated hypotension and that its symptoms may be improved in a subset of patients by therapy directed at this abnormal cardiovascular reflex. There are conditions that explain the presence of severe fatigue and, therefore, preclude the diagnosis of CFS. These include past or current psychiatric conditions of major depression with melancholic or psychotic

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--> features; delusional disorders of any subtype; bipolar affective disorder; schizophrenia of any subtype; dementias of any type; anorexia nervosa; and bulimia. The following comorbid conditions do not exclude CFS: Any condition defined primarily by symptoms that cannot be confirmed by diagnostic laboratory tests (e.g., fibromyalgia, anxiety disorders, somatoform disorders, nonpsychotic or nonmelancholic depression, neurasthenia, panic disorder, and multiple chemical sensitivity disorder). Any condition under specific treatment sufficient to alleviate all symptoms related to the condition for which the adequacy of treatment has been well documented (e.g., hypothyroidism in which the adequacy of replacement hormone has been verified by normal thyroid-stimulating hormone levels and asthma in which the adequacy of treatment has been determined by pulmonary function and other testing). Any condition that was previously treated with definitive therapy before the development of chronic symptomatic sequelae (e.g., Lyme disease or syphilis). Any isolated and unexplained physical examination finding or laboratory or imaging test abnormality that is insufficient to strongly suggest the existence of an exclusionary conditions (e.g., an elevated antinuclear antibody titer that is inadequate to strongly support the diagnosis of a discrete connective tissue disorder without other laboratory or clinical evidence, Fukuda et al., 1994). The objectives of therapy for CFS are to help the patient develop realistic goals and expectations through education, to provide symptomatic relief, and to preserve and improve the patient's ability to function (Fukuda and Gantz, 1995). A necessary component of this therapy is for the provider to acknowledge that the patient's suffering is real. Therapy for CFS patients includes provision of symptomatic treatment such as medications for depression, anxiety, pain, sleep problems, and allergies. To prevent further disability it is important for the patient to engage in graded exercise and physical therapy. Cognitive behavioral therapy (CBT) is also used in an attempt to alter attitudes, perceptions, and beliefs that can contribute to maladaptive behavior. Patients need to establish realistic goals for managing their lives, to apply stress reduction techniques, and to restructure their activities to better accommodate their needs and condition. The longer a patient has been ill with CFS, the less likely he or she is to get better. Therefore, early diagnosis and treatment are extremely important.

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--> FIBROMYALGIA Fibromyalgia (FM) is a disorder of widespread pain, tenderness, fatigue, sleep disturbance, and psychological distress (Wolfe et al., 1995). Additional clinical features may include irritable bowel syndrome, paresthesias, headache, irritable bladder, somatization, and social dysfunction. Problems with the classification and diagnosis of fibromyalgia led to development of the following criteria by the American College of Rheumatology. There must be a history of widespread pain. Pain is considered widespread when all of the following are present: pain in the left side of the body, pain in the right side of the body, pain above the waist, and pain below the waist. In addition, axial skeleton pain (cervical spine or anterior chest or thoracic spine or low back) must be present. Shoulder and buttock pain is considered pain for each involved side. ''Low back" pain is considered lower segment pain. There is pain on digital palpation in 11 of the 18 following sites of tender points: Occiput: bilateral, at the suboccipital muscle insertions. Low cervical: bilateral, at the anterior aspects of the intertransverse spaces at C5-C7. Trapezius: bilateral, at the midpoint of the upper border. Supraspinatus: bilateral, at origins, above the scapular spine near the medial border. Second rib: bilateral, at the second costochondral junctions, just lateral to the junctions on upper surfaces. Lateral epicondyle: bilateral, 2 cm distal to the epicondyles. Gluteal: bilateral, in upper outer quadrants of buttocks in anterior fold of muscle. Greater trochanter: bilateral, posterior to the trochanteric prominence. Knee: bilateral, at the medial fat pad proximal to the joint line. Fibromyalgia patients can be differentiated from controls by testing their pain threshold or tolerance anywhere on the body, not just on tender points (Clauw, 1995). Fibromyalgia patients have allodynia, a reduction in pain threshold, as well as hyperalgesia, which means that things that hurt are more

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--> hurtful. Patients with fibromyalgia may report pain only in certain areas, however, because those areas are the most troublesome. Part of the diagnostic process must, therefore, carefully elicit information about all painful areas. This may be accomplished by using a pain diagram or by asking repeatedly about various body regions. The major feature distinguishing fibromyalgia from other disorders is tenderness (or sensitivity). The two methods for measuring tenderness are digital palpation and dolorimetry. The amount of force used in palpation is important because too large a force will elicit pain in someone without fibromyalgia, whereas too little force may miss pain in someone with fibromyalgia. It has been suggested that the best method for determining the amount of pressure required is to palpate "normal" individuals of the same build and stature as the suspected fibromyalgia patient. Although questions about the validity of palpation can be raised, studies have shown that trained examiners can reach high levels of agreement in the identification of patients with and without fibromyalgia (Wolfe et al., 1992). Dolorimetry is a technique that uses a rubber endplate with a spring-loaded force gauge. This gauge is pressed on the tender point site. As the pressure is changed, patients are asked to note when they feel a change from pressure to pain. Although dolorimetry would appear to be a more reliable approach than digital palpation to measuring the pain threshold because it eliminates examiner variability in both the amount of pressure used and the interpretation of patient response, data analyses indicate that both digital palpation and manual palpation are more accurate diagnostic approaches. This may be because the gauge is pressed on one site at a time, whereas during palpation, the examiner can feel around for the exact place to exert pressure. In addition, the rolling motion involved in feeling for the correct site may find a tenderness not noted by direct pressure alone (Wolfe, 1994). In addition to pain, there are other signs and symptoms common to patients with fibromyalgia. In a 1990 ACR study of criteria for the classification of fibromyalgia, 81% of the patients complained of fatigue and 74% complained of sleep disturbance. Psychological factors are also important. Of patients with fibromyalgia, 30% report the symptom of depression (Wolfe, 1994). It is important to point out that fibromyalgia cannot be explained solely as a psychiatric illness like depression, however. Family members of fibromyalgia patients have a higher-than-expected rate of fibromyalgia. In addition, trauma, either physical or emotional, may precipitate one-third of the cases of fibromyalgia. Infections such as Lyme disease and HIV and connective tissue disorders such as systemic lupus erythematosus and rheumatoid arthritis frequently coexist with fibromyalgia. Aerobic fitness may be a positive modulating factor, that is, it may lessen the negative effects of the condition (Clauw, 1995).

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--> Many investigators now agree that aberrant central nervous system mechanisms are likely to be responsible for the majority of clinical findings in fibromyalgia. A central nervous system genesis explains not only the high incidence of nonmusculoskeletal symptoms in a wide variety of organs and tissues, but also the affective disorders and neurological features which occur in this condition (Clauw, 1995). Available treatments for fibromyalgia range from conventional medication therapy with tricyclic antidepressants to nonconventional interventions such as biofeedback. It appears that there is short-term benefit in the treatment of fibromyalgia syndrome with tricyclic agents, but this has not proved longlasting in placebo-controlled trials. A relatively small proportion of patients (about 25% to 30%) have significant improvement. The majority have little or no improvement. In addition to commonly used pharmacologic therapies, patient education, reassurance, and an exercise program can each play an important role in relieving the symptoms associated with this musculoskeletal syndrome. Patient education is important in assuring patients that they have a common, nonthreatening condition. Such education should include a description of how the diagnosis was made, what the condition represents, and the entire therapeutic plan. In addition to education, exercise has been shown to contribute to improvement in pain threshold scores. Electromyography (EMG) biofeedback has been tested in controlled trial settings. Ferraccioli et al. (1987) conducted a controlled study of biofeedback in 12 patients and reported a 50% clinical improvement in 9 of those patients, sustained for six months. A study of electroacupuncture showed improvement in the active treatment group, but limitations to the study include no measure of functional or psychological status, lack of specification of time of follow-up assessment, the fact that patients may not have been optimally blinded, and no determination of whether electroacupuncture is equivalent to acupuncture. It appears that whereas the most effective short-term treatment for fibromyalgia is antidepressant therapy, the long-term efficacy of treatment remains elusive. MULTIPLE CHEMICAL SENSITIVITY Multiple chemical sensitivity (MCS) is a diagnosis given to patients who, in response to a chemical exposure that is tolerated by most individuals, exhibit a variety of symptoms that have no apparent organic (or physiologic) basis. MCS is reported to result from a single episode or recurring episodes of a chemical exposure, such as solvent or pesticide poisoning, but it also arises without reports of untoward initial exposure. There is very little agreement on what the symptoms represent, and no definition has yet been endorsed for clinical use by

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--> a body of physicians. The American Medical Association (AMA) and the American College of Physicians have both considered the general topic but have not yet recognized a specific disease entity or definition. Cullen's definition of MCS, primarily for research purposes, appears to be the most widely accepted. The definition allows physicians to distinguish MCS from other clusters of commonly experienced symptoms (Sparks et al., 1994a. This definition has four characteristics: MCS is acquired in relation to some documentable environmental exposure that may initially have produced a demonstrable toxic effect. This aspect excludes patients with long-standing health problems who later attribute certain symptoms to chemical exposure. Symptoms involve more than one organ system, and they recur and abate in response to predictable environmental stimuli. Symptoms are elicited by exposures to chemicals that are demonstrable but very low (perhaps several standard deviations below the average exposures known to cause toxic or irritant health effects in humans). The manifestations of MCS are subjective. No widely available test of organ system function can explain the symptoms, and there is no objective evidence of organ system damage or dysfunction. The syndrome may be severely distressing and functionally disabling, however, because patients increasingly attempt to avoid chemical exposures. The chemicals most closely associated with the majority of initiating episodes are organic solvents, pesticides, and respiratory irritants. This could be because of the widespread use of these materials. The other common setting in which many cases are reported is in buildings with indoor air problems (Cullen, 1997). There are many theories of the etiology of multiple chemical sensitivity. One perspective has focused on the relationship between the mucosae of the upper respiratory tract and the limbic system, especially the linkage in the nose. MCS patients typically report heightened odor sensitivity. Findings suggest that MCS patients do not detect odors at lower thresholds than others, but they may respond more markedly once odors are detected. The relationship of this finding to reports of inflammatory nasal pathology and increased nasal resistance is unexplored, but the pathologic findings require confirmation with controlled studies. Others have suggested that MCS might be related to a disturbance of the immune system. No controlled and blinded studies have been published demonstrating a consistent pattern of alteration in immune parameters in MCS patients after chemical exposure (Sparks et al., 1994a). Another hypothesis is that chemical exposures produce toxic free radicals that cause cell membranes to

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--> release inflammatory mediators. No scientific data have been put forth to support this theory, however (Sparks et al., 1994a). Another theory is that psychological mechanisms explain MCS. It has been proposed that MCS may be a manifestation of the human response to stress or a conditioned response to an initial toxic experience (Jewett, 1992). Some have hypothesized that MCS is a late-life response to early childhood traumas such as sexual abuse. Some investigators argue that MCS is a misdiagnosed psychiatric disease such as depression, anxiety disorders, somatization disorders, or other common psychiatric disorders (Sparks et al., 1994a). Many scientists, physicians, and others have postulated that MCS is, in many ways, a belief system promoted by clinical ecologists and those sympathetic to their views and followed by medically unsophisticated persons. As part of this scenario, MCS patients view themselves as victims of external and uncontrollable factors, and they reject the concept that symptoms are not indicative of severe disease and may have psychological components. A factor that may contribute to this belief system is the increasing concern of the public regarding environmental pollution and the health effects of exposure to manmade chemicals (Sparks et al., 1994a). Although a great deal of literature can be found on the pathogenesis of MCS, there is little clinical or experimental evidence that supports strongly any of the views put forth. The available evidence shows that patients diagnosed with MCS are very heterogeneous and that particular health belief models, concurrent psychiatric illness, and psychologic stress characterize a vulnerable group of people who then develop a sensitivity to odors or low-level chemical irritants (Sparks et al., 1994b). Despite the lack of agreement on etiology, clinicians can still help affected patients with their symptoms. There are no laboratory findings that are characteristic of MCS. To consider this diagnosis, one must take a history and elicit both the symptoms and the fact that they wax and wane with exposure to real agents that are tolerated by most people. Diagnostic testing is done primarily to rule out other illness in the differential diagnosis. Diagnostic evaluation of the suspected MCS patient includes the following: History Detailed exposure history (workplace and other environmental exposures) Industrial hygiene data (Material Safety Data Sheets, results of exposure monitoring, etc.) Current and past medical illnesses and results of previous diagnostic work-ups and treatments Review of prior medical records

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--> B. Physical examination to rule out other illnesses in the differential diagnosis C. Consultation Occupational and environmental medicine specialist Psychiatrist Other specialists as appropriate to rule out other medical conditions in the differential diagnosis D. Other Symptom diary (this can cause people to be overly focused on things they might otherwise ignore) Short-term removal from exposure The focus of treatment is to acknowledge that the symptoms are real and distressing even if there is no evidence of observable organic pathology. The goal of therapy is the control of symptoms. Success depends on the patient's improved understanding of the role stress plays in exacerbating symptoms and on the acquisition of skills for coping with the impact of the illness on daily life (Sparks et al., 1994b). Treatment should be individualized but should include enhancing the patient's sense of control over workplace or home stressors. Approaches to reducing stress have included massage, physical therapy, meditation, or regular exercise. The patient should be reassured that MCS is not fatal and is not associated with signs of progressive disease. A recommendation for complete avoidance of chemical exposures is not indicated because there is no evidence for a cumulative toxic injury and it is impossible to accomplish. Treatment could also include medication to control symptoms, an increase in physical and social activity, and treatment of other coexisting medical illnesses. It is very important to treat coexisting psychiatric manifestations such as depression and panic attacks. Such treatments may be helpful in controlling symptoms no matter what the etiology. CONTROVERSIES AND OVERLAP Patients with CFS, fibromyalgia, and MCS have many symptoms in common. According to some investigations, these conditions may represent overlapping clinical syndromes. In a study by Buchwald and Garrity (1994), it was found that 70% of patients with fibromyalgia and 30% of those with MCS met the criteria for CFS. A study by Hudson et al. found that 42% of fibromyalgia patients have met the criteria for CFS (1992), and research conducted by Wysenbeek et al. (1991) found that 21% of FM patients met CFS

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--> criteria. Goldenberg et al. (1990) found that 70% of patients diagnosed as having CFS met the ACR criteria for fibromyalgia. There are other disorders that overlap with CFS. For patients with TMD, or temporomandibular disorder (also known as TMJ arthritis), almost 60% have the CFS symptom of fatigue for more than six months (Buchwald and Garrity, et al., 1994) and 30% meet the second part of the definition, which is reduced activity. Another overlapping syndrome on which little has been published is Sjögren's syndrome, an autoimmune disorder. One study (Calabrese et al., 1994) produced results that seemed to indicate there was a subset of CFS patients who have a Sjögren's-like syndrome, with dry eyes, dry mouth, and at least some of the laboratory abnormalities seen in Sjögren's syndrome. The cardinal features of these illnesses are chronic regional or chronic widespread pain in the absence of nociceptive input, fatigue, and dysfunction of visceral organs or sensory amplification. Individuals who have multiple chemical sensitivity, for example, sometimes find that they are sensitive to many kinds of sensory input such as bright lights and loud noises. Therefore, if one defines a group of individuals in the population that has a high degree of pain or that has a high degree of fatigue or any of these symptoms, many of the individuals will also have a number of other symptoms. However, it is difficult to define the degree of pain or to rate the pain as to intensity. Fatigue is likewise a problem. Accurate tools to quantify fatigue have yet to be developed and accepted. Therefore it is difficult to define a pathological degree of fatigue. Anywhere one decides to draw the line results in an arbitrary distinction. The minor symptoms (headaches, constipation, etc.) are also problematic. A number of population-based studies have shown that the more of these symptoms individuals have, the more likely they are to have psychological or psychiatric comorbidities. Whatever diagnostic label is arrived at, patients in this spectrum of illness will have a higher than normal incidence of things such as tension and migraine headaches, affective disorders, TMD, irritable bowel syndrome, and so on. Fibromyalgia is a diagnosis which defines an extreme of pain and tenderness experienced by 3% to 4% of the general population. CFS defines a smaller percentage of the population that is most fatigued. In reality, fatigue and pain or tenderness in the population occur on a continuum. What is seen for all of these different symptoms is that they occur over a wide continuum in the population and that current definitions attempt to draw a line somewhere and say that one side of the line represents illness and the other, wellness.

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