INTRODUCTION

Medically unexplained symptoms (MUS) such as chronic pain and fatigue are a critical public health issue for the Veterans Health Administration (VHA) and TheDepartment of Defense (DoD) On a broader level, physical symptoms account for more than half of all outpatient visits each year in the United States—an estimated 400 million visits. The data collected from general population surveys help to clarify the types and frequency of physical symptoms experienced in the general population:

Table 1. Prevalence of Physical Symptoms

Physical Symptoms	Prevalence in the General Population	Prevalence Among Survey Respondents
Fatigue	22%	58%
Joint pain	26%	59%
Headaches	21%	37%
Sleep Difficulties	15%	35%
Dyspnea	14%	32%
Abdominal Pain	11%	24%

[Kroenke, & Mangelsdorf, 1989; Kroenke et al., 1990, Kroenke & Price, 1993, Kroenke et al., 1994]

The National Ambulatory Medical Care Survey (NAMCS) data of 1989 similarly found that patient concerns of fatigue, headaches, joint pains, and skin rashes resulted in an estimated 47.6 million outpatient visits. The estimated number of outpatient visits for fatigue was 7 million; for headaches, 9.6 million; for joint pains, 17 million; and for skin rashes, 14 million. In addition, it was found that many patients experienced more than one symptom.

Other studies have shown that MUS are often treatment refractory and associated with a high proportion of population-wide disability and health care utilization (Escobar et al., 1998; Katon et al., 1991b).

For military personnel, veterans, and their families, MUS take on even greater importance. Concerns of a “Gulf War Syndrome,” putatively caused by wartime exposures, have served as a stark reminder of the challenges that medically unexplained physical symptoms will pose for clinicians, response organizations, and scientists in the event of future military action, terrorist threat, or technological disaster.

Fortunately, there were relatively few combat-related injuries and diseases during the Gulf War conflict; however, up to 45 percent of deployed veterans (as compared to 15 percent of non-deployed veterans) developed a constellation of symptoms and syndromes including muscle and joint pain, fatigue, memory problems, headaches, and gastrointestinal complaints (Fukuda et al., 1999). This experience was not unique to U.S. troops. Veterans of this conflict from the United Kingdom experienced a similar increase in this spectrum of illness (Unwin et al., 1999).

This experience was also not unique to the Gulf War. For example, after World War I many returning veterans described chronic, debilitating physical symptoms that they attributed to chemical exposures incurred during months of trench warfare (Straus, 1999); after Vietnam, hundreds of thousands of veterans sought evaluation for concerns related to agent-orange (dioxin) exposure (IOM, 1999); and the concerns of a “Balkan War Syndrome” [Rogers, 2000] after the peacekeeping in Croatia [National Defense, 2000]. These experiences reinforce the importance that those of us who care for military personnel, veterans, and their families must become skilled at caring for MUS and sometimes engage in the public health debate that accompanies them—debate that often heightens the level of concern and exacerbates the degree of suffering and disability associated with them.

Several expert panels have been convened to examine these illnesses. There is some agreement that this is not a single illness, but rather a constellation of symptoms similar in form to fibromyalgia (FM) and Chronic Fatigue Syndrome (CFS) [Aaron et al., 2001].

Medically Unexplained Symptoms (MUS): Solution to a Confusing Nomenclature

A major obstacle to understanding MUS is the confusing terminology sometimes applied to them. Clinicians, scientists, symptomatic individuals, the media, employers, and other groups frequently apply labels to unexplained symptoms for different purposes. These labels may communicate an implied pathogenesis, such as Chronic Fatigue Syndrome (infectious), certain low-level chemical sensitivities (allergic), somatoform disorders (psychiatric), and Fibromyalgia (rheumatologic). This VHA/DoD guideline will rely on the more generic terms "medically unexplained symptoms" or "unexplained symptoms" to describe physical symptoms that provoke care-seeking, but have no clinically determined pathogenesis after an appropriately thorough diagnostic evaluation (i.e., signs found on examination or laboratory findings) (Engel and Katon, 1999).

A General Approach to CFS, FM, and MUS Management

At present, the treatment of MUS, CFS, FM, and related syndromes is as much an art as it is a science. While it is difficult to reduce the management of MUS to a simple paradigm or single algorithm, there is increasing agreement that treatment strategies have many common elements. Often, differences in treatment approaches may be due to differing traditions and theoretical perspectives across clinical disciplines, rather than to scientific research. In keeping with these observations and the need to recommend effective therapies for military personnel and veterans with MUS, the VHA and DoD have partnered in an effort to develop a clinical practice guideline (CPG) for unexplained chronic pain and fatigue.

The VHA/DoD Working Group did not assume that a single algorithm was possible for all MUS. Instead, the Working Group first developed separate algorithms for CFS and FM. Then the two algorithms were juxtaposed and similarities and differences were identified. In the therapy intervention section of the guideline, the evidence for the two conditions was separated into evidence tables, allowing the reader to quickly identify recommendations that are common for both conditions and those restricted to only one condition. The strength of the treatment recommendations and the supporting evidence supporting remains separated for the two conditions, so that readers may reconstruct and evaluate the thought processes underlying the recommendations.

There is wide appreciation within the Working Group that CFS/FM is part of a continuum of syndromes that providers in different clinical specialties see in their daily practice. Although evidence is often lacking regarding how best to manage different segments along the continuum, CFS/FM offers an excellent starting place for formulating tentative management recommendations. Therefore, the existing evidence for and against various therapies in CFS/FM was used to suggest potentially effective approaches for the rest of the continuum. In a few places, evidence gleaned from clinical trials examining therapies for similar “overlapping” symptom syndromes (e.g., irritable bowel syndrome, mechanical low back pain, somatization disorder, and other chronic pain conditions) was used to formulate treatment recommendations in the absence of more relevant evidence.

Goals of the Guideline

The VHA/DoD Clinical Practice Guideline on the Management of Medically Unexplained Symptoms: Chronic Pain and Fatigue is intended to assist medical care providers in all aspects of patient care. The system-wide goal of evidence-based guidelines is to improve the patient’s outcome. The overall expected outcome of successful implementation of this guideline is to:

· Formulate an efficient and effective assessment of the patient's complaints.

· Optimize the use of therapy to control symptoms.

· Minimize preventable complications and morbidity.

· Achieve satisfaction and positive attitudes regarding the management of chronic unexplained illness

The current guideline represents a significant step toward achieving these goals for patients in the VHA and DoD. However, as with other CPGs, remaining challenges involve developing effective strategies for guideline implementation and evaluating the effect of guideline adherence on clinical outcomes.

The guideline is not intended to serve as a standard of care. Standards of care are determined on the basis of all clinical data available for an individual case and are subject to change as scientific knowledge and technology advances and patterns evolve. The guideline is based on information available at the date of publication, and is intended to provide a general guide to best practice. However, it should be emphasized that evidence-based clinical practice involves using of the best available research evidence, but also exercising of the practitioner’s clinical judgment, to take into account individual patient preferences. The guideline can assist care providers, but the use of a CPG must always be considered as a recommendation, within the context of a provider’s clinical judgment, in the care for an individual patient.

For the Future

Patients with MUS are sometimes considered "difficult." In large part, this is because clinicians are unable to make the patients feel better and their demands exceed the capabilities of conventional medical care. When combined with loss of function, loss of control and support, and high levels of disability, this illness is among the most frustrating, both for patients and providers. The implementation of this guideline will lead to better care, earlier recognition, better patient education, and effective multi-modal management. If this is accomplished, patients with CFS/FM can still lead a relatively rewarding life.

The VHA and DoD are developing a variety of clinical tools for implementing this guideline and a set of indicators to measure their impact on the quality of the related care. Modifications to the guideline will undoubtedly be necessary, as a result of lessons learned and findings from new clinical research are disseminated. The developers believe that this guideline should always be considered “a work in progress."

Key Points

1. Establish that the patient has MUS.

2. Obtain a thorough medical history, physical examination,
and medical record review.

3. Minimize excessive diagnostic testing.

4. Identify treatable cause (conditions) for the patient’s symptoms.

5. Initiate early therapy interventions.

6. Determine if the patient can be classified as Chronic Multi-Symptom
Illness (CMI) (i.e., has two or more symptoms clusters: pain, fatigue,
cognitive dysfunction, or sleep disturbance).

7. Negotiate treatment options and establish collaboration with the patient.

8. Provide appropriate patient and family education.

9. Maximize the use of non-pharmacologic therapies:

· Graded aerobic exercise with close monitoring.

· Cognitive behavioral therapy.

10. Empower the patient to take an active role in their recovery.

Editorial Panel Of The Working Group

Mark Brown, PhD

Director, Environmental Agents Service

Department of Veterans Affair

Steven Hunt, MD

Director Gulf War Veterans Clinic

Puget Sound VA Health Care System

Daniel J. Clauw, MD

Chief, Division of Rheumatology

Associate Professor of Medicine and Ortheadics

Kurt Kroenke, MD

Professor of Medicine

Regenstrieif Institute

Tim Corcoran, Lt Col, USAF

Family Practice (PCM) IM-IT

Clinical Program Policy Office

Ralph Richardson, PhD

Clinical Psychologist

Co-Director, Gulf War Veterans Clinic

Cathy Ellis, PT

Director, Inpatient PT & OT

National Rehabilitation Hospital

James R. Riddle, DVM, MPH, Lt Col, USAF

Program Director, Military Public Health

Office of the Assistant Secretary of Defense

Charles C. Engel, Jr., MC, LTC, USA

Chief, Deployment Health Clinical Center

Associate Professor of Psychiatry

Michael Roy, LTC, MC, USA

Associate Professor of Medicine

USUHS, Department of Medicine

Nelson Gantz, MD

Chief, Infectious Diseases, Pinnacle Health

Clinical Professor of Medicine

Arte Shelton, MD

VA Consultant

Office of Public Health

Facilitator:

Oded Susskind, MPH

Medical Education Consultant

members of The Working Group

ANNOTATIONS

A. Patient with Medically Unexplained Symptoms (MUS)

OBJECTIVE

Identify patients with persistent symptoms not explained by a known medical etiology.

ANNOTATION

Patients managed by this guideline have symptoms that remain relatively unexplained after an appropriate medical assessment that includes focused diagnostic testing (Kroenke et al., 1990; Kroenke & Price, 1993; Kroenke & Mangelsdorf, 1989). Patients are often given multiple labels that lack a well-defined disease explanation. Usual clinical features include a relative lack of objective signs and a chronic symptom course often marked by exacerbations, remissions, and recurrences. Therefore, clinical management must be based largely upon patient report, rather than specific findings on clinical examination or diagnostic testing (Engel & Katon, 1999a). A compassionate approach to patients with medically unexplained symptoms (MUS) is essential (Engel & Katon, 1999b).

B. Obtain Additional History, Physical Examination, Mental Status Examination (MSE), and Psychosocial Assessment

OBJECTIVE

Obtain comprehensive patient data to rule out alternative explanations for unexplained symptoms.

ANNOTATION

A thorough and early review of of all sources of information ~~the following items c~~can help in validating the patient’s health concerns, while communicating care and understanding—the necessary building blocks to an effective patient-clinician partnership. Sources of information include the following:

· All medical records

· Medical history and psychosocial assessment

· Review of systems

· Physical examination and mental status examination (MSE)

· Routine test results

· Standard health assessments

Additional medical history

In obtaining a medical history, the clinician should focus on key symptoms that may suggest a well-defined disease explanation.

Physical examination

Patients with unexplained symptoms have often been examined several times in the past. However, important details may have been overlooked due to time constraints or the frequency that clinicians encounter such complaints in the absence of objective findings. Setting aside time for a detailed and thorough examination is critical for the assessment and may also help in building an alliance with the patient, who in many cases was seen by several clinicians.

Mental Status Examination (MSE)

A careful MSE should be performed, including assessment of appearance, behavior, mood and affect, cognition, thought content and processes, and insight and judgment. A useful screen for cognitive impairment in elderly patients consists ofF four questions from the Mini-Mental State Examination (MMSE) (Koenig, 1996) (i.e., orientation to time, orientation to place, memorizing and repeating three non-related items, and spelling “world” backwardss).

Psychosocial Assessment

A psychosocial assessment is critical in evaluating the patient with unexplained symptoms. It should include a screening for suicidal ideation and substance use disorders. The mental status evaluation should include observation of affect, thinking, judgment, and memory.

The Patient Health Questionnaire (PHQ) is an excellent screening tool for assessing ~~for~~ the presence of the most common psychiatric conditions associated with complaints of fatigue: depression, symptoms, and anxiety (Spitzer et al., 1999; Spitzer et al., 1994). ~~Additionally, the~~ PHQ also screens for alcohol abuse or dependency, binge eating disorders, and bulimia nervosa.

C. Are Unstable or Urgent Condition(s) Present?

OBJECTIVE

Identify patients that are unstable and need immediate treatment.

ANNOTATION

Unstable or urgent conditions represent situations that mandate immediate attention. A complete discussion of diagnosis and management of the entire range of possible urgent conditions is beyond the scope of this guideline. These conditions are generally recognized and managed by the astute primary care clinician.

Some potentially unstable or urgent conditions include (but are not limited to) the following:

Suicidal ideation or psychosis
Objective evidence of joint swelling
Fever (over 101.1 degrees F/38.4 degrees C)
Significant weight loss
Focal findings on neurological examination
Severe anemia or elevated white blood cells

D. Clarify the Symptoms; Build Therapeutic Alliance; Schedule Additional Appointments of Longer Duration

OBJECTIVE

Obtain detailed information on the patient’s symptoms and health concerns, allowing adequate time to enhance the patient's trust and faith in the clinician.

ANNOTATION

Clarify The Symptoms

Patients who present with unexplained pain or fatigue often carry a cluster of symptoms that must be understood as accurately as possible. Taking an accurate history is an essential part of the diagnostic work-up. Questions that may prompt patients to provide important attributes of their symptoms are summarized in the following table.

Table 1. Clarification of Symptoms

Symptom Attributes	Questions
Duration	· Has the symptom existed for days, weeks, or months? · Has the symptom occurred only intermittently? · Particularly with regard to pain and fatigue, can the patient define if these symptoms occurred only two or three days per month or constantly? · Is the symptom seasonal? · Are there times of the day when the symptom is worse?
Onset	· Can the patient recall exactly how the symptom began? · Were there triggering events, either physical or emotional? · Was the onset subtle and gradual, or dramatic and sudden? · Have the triggering events tended to be the same over time or are there changing patterns?
Location	· Is the symptom localized or diffuse? · Can the patient localize the symptom by pointing to it? · If the pain is diffuse, does it involve more than one body quadrant?
Co-morbidity	· Does the patient have any diagnosed co-existing illnesses? · What is the time relationship between the onset and severity of the co-existing illnesses and the symptoms of fatigue and/or pain? · What are the symptoms other than pain and/or fatigue? · Are there co-morbid diagnoses? · Are there changes in the patient’s weight, mood, or diet?
Previous episodes	· If the symptoms are episodic, what is the pattern in regard to timing, intensity, triggering events, and response to any prior treatment?
Intensity and impact	· How severe are the symptoms (use the 1 to 10 Numerical Rating Scale (NRS))? · Ask the patient to describe any new limitations they have experienced compared to their usual life-style, including limitations in physical endurance or strength (e.g., climbing stairs, shopping, and amount or quality of their sleep).
Previous treatment and medications	· Exploring this aspect of the history may be complicated and require obtaining prior medical records, or having an authorized telephone conversation with the prior treating clinician. Ask the patient to bring in their medication bottles on a subsequent visit and document the exact names of the medications. Find out which medications have/have not been helpful.
Past medical, surgical and psychological history	· This area includes chronic and major acute illnesses and injuries, allergies, surgical procedures, and hospitalizations. The psychological history may take several visits to clarify, depending upon the ease with which the patient can articulate their emotional status and past and present issues. Explore stressors such as occupational and family issues.
Patient perception of symptoms	· Often omitted from the history-taking are questions designed to gain some understanding of what the patient believes is happening. Ask the patient about their hunches and fears.

DISCUSSION

Duration

The duration of the symptoms until time of presentation is variable and patients may have spent years seeing numerous clinicians and undergoing extensive evaluations without ever obtaining a diagnosis. Many patients may relate the onset of their symptoms to a significant event (e.g., severe illness, trauma, military mobilization, and viral illness). Some patients may present with symptoms after sustaining central/axial skeletal trauma, such as a motor vehicle accident with resultant whiplash.

Exploring the history and clarifying the details may require several visits. However, the more the clinician can create an atmosphere of calmness and interest in the details, the more likely it is that important aspects of the history will be elicited. Details that may not seem important to the patient to mention in a hurried history may emerge in a subsequent or follow-up visit and provide important clues in determining a diagnosis.

Location

Pain location is important as it may provide useful information to help guide further assessment and treatment. Asking patients to indicate on their bodies where they feel pain can help to assess the distribution (location) of pain. It is also useful to employ a standard pain drawing, consisting of a line drawing outline of the front and back of a human body (see Section C).

Co-morbidity

Other chronic illnesses may occur as co-morbid conditions, including:

· Thyroid disease

· Rheumatic disease

· Sleep apnea

· Neurological disease

· Depression

Irritable bowel syndrome, migraine headaches, and multiple-chemical sensitivity occur more frequently in patients with Chronic Fatigue Syndrome/Fibromyalgia (CFS/FM). The elderly individual also has a higher risk for the presence of malignancy, which should be kept in mind during the evaluation. It is important not to ignore co-morbidities that may represent a true underlying condition that will require treatment.

Previous episodes

The patient may have had prior episodes of similar symptoms in the past, as well as prior treatments.

Patient perception of symptoms

Patients should be given the opportunity to relate their experiences and complaints, at each visit, in their own way. Although time-consuming and likely to include much seemingly irrelevant information, this has the advantage of providing considerable information concerning the patient’s intelligence, emotional make-up, and attitudes about their complaints. This also provides patients with the satisfaction that they have been "heard-out" by the clinician, rather than merely being asked a few questions and exposed to a series of laboratory tests based on "high technology."

As the patient relates the history, important nonverbal clues are often provided. The clinician should observe the patient’s attitude, reactions, and gestures while being questioned, as well as his or her choice of words or emphasis. The impact from the symptoms may range from annoying to totally disabling and patient perceptions regarding the cause and impact are important to understand in managing the disorder. Stressors such as occupational and family issues should also be explored.

The BATHE technique (Servan-Schreiber et al., 2000) provides a time-efficient way to address the impact of patients’ symptoms on their level of function. The BATHE technique addresses the following topics:

· Background: “What is going on in your life?”

· Affect: “How do you feel about it?”

· Trouble: “What troubles you the most about the situation?

· Handle: “What helps you handle that?”

· Empathy: “This is a tough situation to be in. Anybody would feel (down, stressed, etc.). Your reaction makes sense to me.”

Build Therapeutic Alliance

~~The initial evaluation by the clinician helps establish trust by demonstrating that the patient and thepatient’s symptoms are taken seriously.~~ Performing a complete history and physical examination that fully clarifies all symptoms helps the clinician in both diagnosing the condition, and in building a therapeutic relationship with the patient. The lack of diagnosis or effective treatment can make the management of patients with unexplained symptoms ~~are~~ challenging. It may also cause frustration ~~to treat and for~~ for both the patient and the provider. A high level of patient trust and faith in the clinician is required in order to maintain continuity of care and continue patient management through regular follow-up appointments. The initial evaluation helps establish a special partnership between the patient and clinician. To strengthen the partnership with the patient, the clinician should (Stuart & Lieberman, 1993):

· Acknowledge and indicate commitment to understand the patient’s concerns and symptoms.

· Encourage an open and honest transfer of information that will provide a more comprehensive picture of the patient's concerns and medical history.

· Indicate commitment to allocate sufficient time and resources to resolving the patient’s concerns.

· Avoid open skepticism or disapproving comments in discussing the patient’s concerns.

At each patient visit, the clinician should consider the following:

· Ask if there are unaddressed or unresolved concerns.

· Summarize and explain all test results.

· Schedule follow-up visits in a timely manner.

· Explain that outstanding or interim test results and consultations will be reviewed during the follow-up visits.

· Offer to include the concerned family member or significant other in the follow-up visit.

DISCUSSION

The clinician’s initial evaluation helps establish a high level of trust by demonstrating that symptoms will be taken seriously. Continuity of care is also essential for building a trusting therapeutic alliance and rapport. Continuity is achieved through regularly scheduled follow-up appointments.

Patients have certain common hopes and expectations when they see a clinician (Marple et al., 1997). Patients want to be listened to, be able to fully express their fears and concerns, and share their burden. They want the clinician to be interested in them as fellow human beings, in a compassionate but nonjudgmental fashion. They expect professional competence and to receive the best in medical science and technology. They want to be reasonably informed as to the probable cause of their concerns and what the future is likely to hold.

Schedule Additional Appointments of Longer Duration

The clinician’s initial evaluation helps establish a high level of trust by demonstrating that the patient’s symptoms will be taken seriously. Continuity of care is also essential for building a trusting therapeutic alliance and rapport. Continuity is achieved through regularly scheduled follow-up appointments that encompass:

· Several appointments

· Extended visits

· Setting aside time to review the medical record and laboratory results

E. Revisit the Medical Record

OBJECTIVE

Clarify the history of the MUS.

ANNOTATION

Review the patient’s medical record for co-morbidities, prior episodes, occurrences of other unexplained symptoms, prior evaluations, and the nature and extent of prior therapy.

The review should include the following:

· Complete medical history

· Family and social history

· Occupational and deployment history

· Exposure to possible risks, hazards, and toxic agents

· Prescription history, including over-the-counter medications and herbs

· Clinical notes

· Other documented history and physical examinations

· Radiological, laboratory, and other ancillary test results

· Effectiveness of previous therapies and reasons for past treatment failures or successes

F. Obtain Focused Diagnostic Tests, If Not Already Done

OBJECTIVE

Identify objective findings that may suggest the diagnosis.

ANNOTATION

After a complete history and physical examination, there are several Australia routine laboratory tests that will assist in completing the patient assessment (CFS Guideline, Medical Journal of Australia, 1997):

· Complete blood count

· Electrolytes

· Blood urea nitrogen

· Creatinine

· Glucose

· Calcium

· Phosphate

· Liver function tests

· Total protein

· Thyroid-stimulating hormone

· Erythrocyte sedimentation rate

· Urinalysis

The clinician also should ensure that health care maintenance is up to date.

The following tests should only be ordered if the history or physical examination results strongly suggest the need (CDC, 1999):

· Serological tests for:

– Epstein-Barr virus

– Lyme disease (in the absence of polyarthritis, history of tick bite, or erythema chronicum migrans)

– Immunologic function testing

· Neuroimaging

G. Can Another Condition or Disease (Including Mood, Anxiety, and Substance Use Disorders) Explain (or Cause) the Symptoms?

OBJECTIVE

Identify patients for whom treatment of cause may resolve the symptoms.

ANNOTATION

After obtaining a detailed history, completing a thorough physical examination, obtaining laboratory test results, and using a screening tool (e.g., the PHQ) the clinician should determine whether an explanatory or causal condition can be diagnosed or whether the symptoms remain medically unexplained.~~When considering depression, the clinician should assess whether the symptoms are causing depression or whether the depression is resulting in physical complaints~~.

The following examples of the patient's description may indicate a related diagnosis. In most instances, the symptoms of CFS can be distinguished from the closely related phenomena of somnolence, muscle weakness, neuromuscular fatigability, depressed mood, or anhedonia.

Table 2. ~~Need to mention in~~ ~~narrative~~Patient's Description of Fatigue or "Tiredness"

Patient’s Description	Clinician’s Interpretation
· Reduced muscle power at rest Difficulty walking or lifting weights	· Muscle weakness (e.g., myopathy or polymyositis)
· Loss of muscle power over time with activity	· Neuromuscular fatigability (e.g., myasthenia gravis)
· Physical and mental fatigue at rest	· Central fatigue (e.g., multiple sclerosis)
· Lack of motivation to commence tasks · Lack of pleasure from tasks undertaken	· Anhedonia (e.g., major depression)
· Daytime sleepiness Short sleep latency	· Somnolence (e.g., sleep apnea or narcolepsy)
· Breathlessness at rest or on exercise	· Dyspnea · Weakness (e.g., airflow limitation, cardiac failure, or anemia)
· Muscle or joint pain · Fever or malaise	· Inflammation (e.g., systemic lupus erythematosus) · Infection (e.g., influenza)

Chronic Fatigue Syndrome CPG Working Group Royal Australian College of Physicians, 1997.

When considering depression, the clinician should assess whether the symptoms are causing the depression or the depression is resulting in physical complaints. Physical illness may cause psychosocial distress through a direct biological link, such as through neurotransmitters involved in both pain and mental disorders. Physical symptoms may cause emotional distress by overwhelming an individual’s ability to cope. Distress may increase unhealthy behaviors that increase the risk of such symptoms. The disordered sleep and changes in autonomic nervous system functioning associated with stress may cause these symptoms. Finally, both mental disorders and MUS may be found together in some people, simply by chance.

DISCUSSION

Studies of patients with MUS indicate high rates of major depression and panic disorder (Goldenberg, 1987; Katon et al., 1985; Katon et al., 1991a; Black et al., 1990; Simon et al., 1990; Hudson et al., 1992; Clauw & Chrousos, 1997). Several mechanisms might account for this correlation (Engel & Katon, 1999b).

Studies indicate that increasing numbers of physical symptoms are accompanied by an increasing likelihood of experiencing anxiety and depressive disorders (Katon & Russo, 1992; Kroenke et al., 1994; Russo et al., 1994; Kisely et al., 1997). For example, in a study using self-reports from a sample of more than 1,000 health maintenance organization enrollees, increasing numbers of pain complaints were strongly associated with elevated levels of anxiety, depression, and physical symptoms that did not cause pain (Dworkin et al., 1990). In a separate study, the percentages of people with anxiety and depressive disorders increased with increasing numbers of physical symptoms (both medically explained and unexplained from the perspective of the interviewer) (Kroenke et al., 1994). Depression and anxiety are consistently associated with MUS across many studies that used several different methods and cross-sectional (Simon & VonKorff, 1991), case-control (Katon, 1988; Katon, 1991b; Sullivan et al., 1988; Walker et al., 1988; Walker et al., 1990), and longitudinal designs (Leino & Magni, 1993; Von-Korff et al., 1993). Katon and colleagues have found that the relationship of physical symptoms to common anxiety and depressive disorders is linear. As the number of anxiety and depressive symptoms or lifetime episodes of these disorders increases, the prevalence and number of MUS also increases (Katon, 1991b).

These data suggest that medically unexplained physical symptoms may sometimes be a marker of psychosocial distress. In occupational medicine settings such as the military, with a younger and medically healthier population than the general population, this effect is probably amplified. With a lower base rate of most diseases, there is a higher likelihood that unexplained symptoms are due, at least in part, to more common and less easily recognized psychiatric disorders, such as anxiety and depressive disorders (Engel & Katon, 1999b).

H. Consider Initiating Symptom-Based Treatment Modalities

OBJECTIVE

Reduce symptoms and promote functioning and well-being.

ANNOTATION

Although the criteria for CFS require six months duration of symptoms prior to making the diagnosis, the initiation of appropriate treatments for unexplained symptoms and for myalgias may be considered earlier.

There is a point in the course of the diagnostic work-up and clinical monitoring at which the symptoms may appear to be "unexplained." The time that elapses in reaching this point varies.

· Early interventions should include restoration of sleep and management of pain.

· The clinician must maintain an ongoing vigilance to the possibility of emerging diagnosable conditions.

DISCUSSION

Clinical medicine typically involves a process of using symptoms, physical findings, and test results to establish a specific disease diagnosis for which a disease-specific treatment intervention will be prescribed (Engel et al., 1998)~~(1)~~. The clinician should keep in mind, however, that in a significant number of clinical encounters, such a specific diagnosis will not be established. (Kroenke & Mangelsdorf, 1989; Schappert, 1992).~~(2;3)~~

In situations involving unexplained symptoms, early intervention may improve prognosis (Working Group consensus) (QE=III). In light of this possibility, and despite the fact that the criteria for making the diagnosis of CFS require the presence of symptoms for at least six months, the clinician should consider ~~the possibility~~ that the symptoms may ultimately fall into the category of unexplained symptoms; appropriate interventions may be initiated within the first three months following presentation. This is also true for myalgias and conditions, such as ~~fibromyalgia~~FM (Buchwald & Garrity, 1994). A meta analysis of 26 studies revealed that among patients in primary care with fatigue lasting <6 months, at least 40 percent of patients improved. As the definition becomes more stringent the prognosis appears to worsen. Consistently reported risk factors for poor prognosis are older age, more chronic illness, a co-existing comorbid psychiatric disorder, and holding a belief that the illness is due to physical causes (Joyce et al., 1997). Similar to the recommended treatments for ~~fibromyalgia~~ FM and CFS, early interventions should address restoring sleep, managing pain, and possibly providing cognitive behavioral therapy (CBT). The approach is oriented toward symptom management and optimization of physical and psychosocial functioning in all realms (Walker et al., 1998)~~(9)~~ ~~(10-17)~~.

EVIDENCE

Recommendations

Source

Early intervention may improve prognosis.

Working Group consensus

QE= Quality of Evidence; R = Recommendation (See Appendix 1)

I. Does Patient Present With 2 or More of the Following: Fatigue, Pain, Sleep Disturbance, or Cognitive Dysfunction?

OBJECTIVE

Identify and describe signs and symptoms for classification of CFS/FM.

ANNOTATION

Chronic unexplained symptoms are very common in the general population. In many instances, these symptoms occur in isolation (e.g., fatigue and headaches). However, it is also common for these symptoms to aggregate in individuals, leading to hypothesized “syndromes” that have been given a variety of terms, such as CFS, FM, and somatoform disorders (see Figure 1 ~~below~~). There are substantial data suggesting that overlapping illnesses have common mechanisms, and respond to similar types of interventions. Careful assessment of fatigue, pain, cognitive difficulties, sleep disturbance, and associated physical symptoms, considering their impact on the patient in isolation and aggregate, will allow the clinician to reach an appropriate diagnosis.

Figure 1. Overlapping Chronic Multi-Symptom Illnesses

Fatigue

~~Fatigue should be differentiated from transient tiredness~~. Persistent fatigue is the primary manifestation of CFS and is present in over 90 percent of FM patients, as well. Patients may describe their fatigue in various ways. It is also ~~also~~ present in otherwise healthy patients and in a wide array of other illnesses (see Table 4). Fatigue should be differentiated from transient tiredness. Patients report a diminished ability to perform mental and physical tasks because of fatigue, and that those tasks increase their fatigue. Fatigue is not substantially improved by rest, including sleep, naps, or cessation of activities. The patient may also ~~also~~ describe sleep disturbance—--unrefreshing sleep that may be characterized by difficulty falling asleep, frequent awakening, abnormal limb movements (such as myoclonus), or sleep apnea.

~~Patients might describe their fatigue in various ways, see, Annotation to box 9:~~

Pain

~~In FMp~~Pain is the primary manifestation in FM and is in very common in CFS~~, it is very common~~. Patients complain of muscle and joint pain, but are usually unable to differentiate between muscle and joint area pain. Pain usually becomes widespread (typically bilateral and above and below the waist) and is poorly localizable (meaning it occurs "all over"). Occasionally patients will complain only of unilateral body pain. The characteristic of widespread pain indicates a central nervous system etiology.

~~The characteristic of widespread pain that is poorly localizable probably reflects a central nervous system etiology. The patient is unable to separate muscle from joint area pain.~~ "Widespread pain" is defined as occurring in at least three quadrants: above and below waist, right and left side of the body, and axial. The pain-drawing methodology may be helpful because it allows the patient to indicate the location of their pain on a line drawing of the human body (Margolis et al., 1986). This method permits a systematic and standard method to assess pain location and determine whether the patient meets the "widespread pain" criteria (see Section C).

On examination there is increased tenderness, often very marked, to palpation in characteristic locations, defined as "tender points" (TPs)—pain on digital palpation ). Although there is controversy regarding the assessment and usefulness of evaluating TPs, three options ~~of tender points~~have been offered:

1. Simple count of the number of TPs, following the procedure as described in the original American College of Rheumatology (ACR) paper (Wolfe et al., 1990). There are a number of problems with the protocol described in this paper because important information was omitted regarding procedural standardization (e.g., patient position and examiner position).

2. Myalgic scores (Baumstark & Buckelew, 1992; ~~Baumstark & Buckelew, 1992~~Tunks et al., 1995)~~Tunks et al., 1995~~, which use a dolorimeter for patients to rate the amount of pressure required for each point to become painful. The "myalgic score" is the sum of the amount of pressure for all aggregated TPs. The average myalgic score can be determined by dividing the summed score by 18. The advantage of using this approach is that there is a greater range of scores, and although the number of positive TPs may not change over time or as a result of treatment, the myalgic score may be responsive to time and treatment.

3. Manual Tender Point Survey (MTPS) (Starz et al., 1997; Okifuji et al., 1997) have the following~~(Okifuji et al., 1997; Starz et al., 1997)~~ advantages: a) it follows a standard protocol and has an instructional booklet and tape, b) it does not require a dolorimeter, and c) it provides a range of scores similar to the myalgic score, while at the same time it permits determination of the absolute number of TPs so that the ACR criteria can be used.

~~The second criteria for the classification of FM using the ACR guidelines is~~: ~~"widespread pain~~,~~" defined as in at least three quadrants:~~ ~~above and below waist, right and left side of the body, and axial.~~ ~~Usually this is not systematically assessed;~~ t~~he pain~~- ~~drawing methodology could be used. This method permits a systematic and standard method to assess pain location and determine whether the patient meets the "widespread pain" criteria.~~

Headache and sore throat are common complaints in patients with CFS. The headache should be of a new type, different from that previously experienced, with a new pattern or severity. Patients often complain of a myriad of other vague pain, unexplained by clinical evaluation, either at the same time or over time. (e.g., urethral symptoms, pelvic pain, tension, or migraine). However, these complaints are not included in the definition of CFS/FM.

Cognitive Difficulties

Neurocognitive difficulties are common in CFS/FM and may include the following:

· Forgetfulness

· Memory disturbance

Problems with concentration

Sleep Disturbance

Poor sleep is a frequent complaint in FM, and some patients have objective abnormalities noted in sleep studies. But even though disturbed sleep likely plays a significant role in symptom expression in some patients, and may contribute to some of the physiologic abnormalities (e.g., low IGF-1), the aggregate data do not support the notion that disturbed sleep alone is causing this illness.

Sleep disturbances, common in CFS, may include u – n-refreshing sleep (i.e., waking up feeling unrefreshed) that may be characterized by difficulty falling asleep, frequent awakening, abnormal limb movements (e.g., myoclonus), or sleep apnea. A shift from regular night-time sleep to day-time naps and a late-night to late-morning sleep cycle is sometimes noted. It is known that chronic disruption of the normal sleep pattern can induce symptoms in healthy volunteers, including fatigue, musculoskeletal pains, irritability and concentration impairment.

Associated Physical Symptoms

While the recognized criteria for CFS/FM emphasize the presence of chronic pain and fatigue, it is nonetheless important to note that patients suffering from CFS/FM generally present a number of physical symptoms that complicate the approach to diagnosis. The clinician who is alert to the possibility of MUS will find it easier to make the diagnosis and not become unduly alarmed. The subjective symptoms associated most frequently with CFS/FM are included in the following table.

Table 4. Associated Somatic Symptoms

Cardiovascular system

· Palpitations

· Raynaud’s phenomenon

Endocrine System

· Generalized fatigue

· Excessive sweating, localized or generalized

· Hypoglycemia

· Dry skin

· Hair loss

Respiratory system

· Allergies

· Dyspnea

· Cough

Musculoskeletal system

· Costochondritis

· Temporo-mandibular dysfunction

· Muscle spasms (including nocturnal myoclonia)

Digestive system

· Dry mouth

· Dysphagia (e.g., “lump” in the throat, difficulty swallowing, and sore throat)

· Dyspepsia

· Irritable bowel (diarrhea or constipation)

Central Nervous system

· Disturbance of mood

· Chronic headaches, migraines

· Generalized dysesthesia (e.g., burning sensation, heat, numbness, chills, pins and needles, subjective sensation of swelling)

· Hypersensitivity to noise, odors and air conditioning

· Insomnia

· Tendency to drop things

· Tinnitis

· Double vision

· Balance problems and dizziness

· Dry eyes or excessive tearing

Genitourinary system

· Irregular menstrual cycles

· Dysmenorrhea

· Irritable bladder (urgency of urination)

J. Document the Diagnosis; Consider Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS), or Chronic Multisymptom Illnesses (CMI)

OBJECTIVE

Assign specific diagnostic labels that may have implications in the clinical course of treatment for patients with MUS.

ANNOTATION

Chronic Fatigue Syndrome

CFS is the current term used to describe a syndrome involving a set of defined (yet in many ways, non-specific) symptoms and behaviors that include, as a defining element, severe disabling fatigue and a combination of associated symptoms including cognitive impairments (memory and concentration), sleep disturbances and musculoskeletal pain. The condition has been described for centuries using a variety of nomenclatures (e.g., febricula, nervous exhaustion, neurasthenia, epidemic neuromyasthenia, benign myalgic encephalomyelitis, royal free disease, and chronic mononucleosis) (Shafran, 1991; Demitrack, 1998). To date, no clear pathophysiology or etiologies have been established, and current evidence points to a heterogeneous and multi-causal pathogenesis (Wilson et al., 1994; Schwartz, 1988; Demitrack & Greden, 1991; Demitrack, 1997). In 1994, an international study group coordinated by the Centers for Disease Control (CDC) established the most widely accepted criteria for case definition of CFS (Fukuda et al., 1994).

A case of chronic fatigue syndrome is defined by the presence of:

Clinically evaluated, unexplained, persistent or relapsing fatigue that is of new or definite onset; is not the result of ongoing exertion; is not alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social, or personal activities.

and

Four or more of the following symptoms that persist or reoccur during six or more consecutive months of illness and do not predate the fatigue:

· Self-reported impairment in short term memory or concentration

· Sore throat

· Tender cervical or axillary nodes

· Muscle pain

· Multi-joint pain without redness or swelling

· Headaches of a new pattern or severity

· Unrefreshed sleep

· Post-exertional malaise lasting >24 hours

Fibromyalgia

FM is the current term used to describe a syndrome involving a set of defined (yet in many ways, non-specific) symptoms and behaviors that include, as a defining element, widespread musculoskeletal pain and tenderness. The condition has been described for centuries using a variety of nomenclatures (e.g., muscular rheumatism, fibrositis, fibromyositis, and psychogenic rheumatism). To date, no clear pathophysiology or etiologies have been established. In 1990, a committee of the ACR established the most widely accepted criteria for case definition of FM (Wolfe et al., 1990). The ACR criteria include the following:

History of widespread pain involving all four quadrants of the body and the axial skeletal

and

Tenderness to digital palpation (9 lb/4 kg pressure) of at least 11 of 18 specifically identified TPs

Concurrent symptomatology is nearly universal and includes fatigue, headaches (both migraine and musculoskeletal), paresthesias, hearing/ocular/vestibular complaints, cognitive difficulties (memory and concentration), “allergic” and chemical sensitivity symptoms, non-cardiac chest pain, palpitations, dyspepsia, irritable bowel syndrome and affective/somatoform disorders (Clauw, 1995)..

Labeling

There is insufficient evidence to allow clinicians to predict the impact that diagnostic labels such as FM syndrome, CFS, multi-chemical sensitivity (MCS), CMI, or Gulf War Illness (GWI) will have on the clinical course of patients with these symptoms. There is evidence, however, to suggest that the clinician should consider the following potential impacts:

· Assigning specific diagnostic labels may have implications in the clinical course for a particular individual with MUS.

· There may also be negative effects of labeling. A diagnostic label may sometimes unnecessarily cause a patient to define him or herself as ill, an effect that could be especially problematic in occupational health care settings.

· The potential risks and benefits of applying a particular diagnostic label to unexplained symptom clusters should be weighed by the clinician and discussed with the patient prior to applying such a diagnostic label.

· The clinician should consider generic approaches to managing ~~medically unexplained symptoms~~MUS; such approaches may be useful, without having to rely on specific diagnostic labels.

K. Summarize the Patient’s Condition; Develop a Treatment Plan

OBJECTIVE

Identify the patient's problems and potential treatment options.

ANNOTATION

Assure that the patient understands the meaning and impact of CFS/FM syndrome on their life and the potential improvement a recommended treatment may offer. A final acceptable treatment plan should be negotiated with the patient and documented in the medical record.

· Prepare a summary of the problems and potential treatment plans prior to meeting the patient.

– Develop a problem list with an assessment of problem severity and urgency for treatment.

– Develop treatment options for discussion with the patient.

· Educate the patient.

– Discuss the general concept of MUS and how problems associated with this diagnosis apply to the patient.

– Evaluate the patient’s understanding.

– Describe treatment options and the associated risks and benefits.

– Describe the prognosis of the illness.

· Collaborate with the patient and determine the patient’s preferences.

– Determine the patient’s goals for recovery.

– Explore and discuss the patient’s beliefs regarding his or her illness.

– Determine if the patient agrees with the priority and severity of the problems and urgency for treatment.

– Determine the level of the patient’s agreement with the recommended treatment or one of the alternative options.

– Determine the patient’s motivation to begin treatment and identify barriers to treatment.

– Obtain the patient’s consent to the treatment plan.

· Empower the patient for self-management.

– Move the responsibility of patient improvement from the treatment team to the patient.

– Encourage a change in life-style, including exercise, diet, sleep hygiene, stress reduction, relaxation training, leisure activity schedule, and pacing.

· Implement the treatment plan.

– Coordinate treatment plan activities.

– Establish a referral and interdisciplinary team approach, if indicated.

· Follow-up.

– Monitor treatment progress and patient improvement.

– Establish a regular follow-up schedule throughout and after treatment.

Role of the Primary Care Manager (PCM)

In the course of the assessment, the primary care provider should also serve as the primary care manage (PCM) and develop a problem list that summarizes the findings of specialty consultations and diagnostic procedures related to the diagnosis of CFS/FM or CMI. The PCM should determine the severity of each identified problem and the impact it will have on the patient’s functional ability and quality of life, so that a baseline can be established against which improvements can be assessed. The PCM should also identify problems for which treatment is most urgently recommended. The most urgent treatments may be defined as those treatments expected to result in the greatest improvement when addressing the most severe problems.

Role of Consultants

The PCM is not expected to directly provide treatment, but is expected to serve as the focal point for a multi-disciplinary approach to treatment that may span the continuum of care, beginning with self-management. The treatment team may include those from whom prior consults have been obtained, such as physical therapy, nutrition, social work, psychology, rheumatology, and significant others within the patient’s social network. The PCM, with patient consent, may find it useful to involve the patient’s employer/supervisor, spouse, and friends in the defined treatment team.

Mental health professionals should provide input into implementing psychotherapies and psychopharmacology in outpatient or partial hospitalization settings. Social workers should help build family and social support networks, or recommend changes in the patient’s living situation, in order to create a positive support network. Within the most intensive treatment setting within the continuum of care, residential treatment may be required to assure the presence of a support network.~~CFS/FM has significant negative impact on the patient’s~~ ~~physical~~, ~~mental~~ ~~and~~ ~~social well-being~~. Multi-disciplinary treatment should cover these three main areas. Interventions expected to improve physical well-being include a graduated exercise regimen (monitored through physical therapy, exercise trainers, and social supports), improved sleep habits, and medication (monitored by the physician). ~~Mental well-being may be improved through individual or group therapy, medication, and creating a supportive social network.~~

SECTION E: INFORMATION SOURCES

APPENDICES

INTRODUCTION

Medically Unexplained Symptoms (MUS): Solution to a Confusing Nomenclature

A General Approach to CFS, FM, and MUS Management

Goals of the Guideline

For the Future

Facilitator:

Oded Susskind, MPH

Additional medical history

Physical examination

Mental Status Examination (MSE)

Psychosocial Assessment

Clarify The Symptoms

Duration

Location

Co-morbidity

Previous episodes

Patient perception of symptoms

Build Therapeutic Alliance

Schedule Additional Appointments of Longer Duration

Recommendations

Source

Fatigue

Pain

Cognitive Difficulties

Sleep Disturbance

Associated Physical Symptoms

Chronic Fatigue Syndrome

Fibromyalgia

Labeling

Role of the Primary Care Manager (PCM)

Role of Consultants