CHRONIC FATIGUE SYNDROME

CHRONIC FATIGUE SYNDROME

Chronic fatigue syndrome (CFS) is an often-misunderstood syndrome that should not be confused with malingering or hypochondriasis.

Patients with CFS are truly suffering from their often-disabling symptoms. It is impossible to successfully treat a patient with CFS unless the clinician believes the patient is genuinely symptomatic. CFS should also not be confused with the isolated symptom of fatigue.

Fatigue is a common patient complaint, whereas CFS has a much lower prevalence.

Definition

CFS is not a new disease; the syndrome has been described since at least the mid-1700s. However, since that time it has been mistakenly ascribed to a number of incorrect pathologic and infectious causes. In the past it has been called febricula, neurasthenia, effort syndrome, DeCosta’s syndrome, myalgic encephalitis, chronic brucellosis, chronic Lyme disease, chronic Epstein-Barr syndrome, total allergy syndrome, chronic candidiasis, and multiple chemical sensitivity syndrome. Most recently it has been falsely attributed to infection with xenotropic murine leukemia virus–related virus (XMRV) and related retroviruses, such as murine leukemia virus (MLV). None of these possible causes has proved to be correct.

In 1988, in an attempt to be descriptive rather than attribute an incorrect etiology to the disease, the term chronic fatigue syndrome was coined. Therefore, the name is relatively new but the syndrome is not. The disease is chronic and fatigue is a cardinal feature, but it is more than being chronically tired. It is a syndrome that includes a number of additional symptoms as noted in Box 1, the working case definition as published by the CDC and then modified in 1992 by the National Institute of Allergy and Infectious Diseases. One note of caution: This case definition is an epidemiologic tool and not a strict clinical tool. It is useful for studying the disease. However, some patients do not completely fit this definition but CFS can nonetheless be diagnosed by a knowledgeable clinician.

Box 1
International Consensus Definition of Chronic Fatigue Syndrome
Chronic fatigue syndrome is a clinically evaluated, unexplained, persistent or relapsing chronic fatigue (lasting more than 6 months)

that is of new or definite onset (has not been lifelong); is not theresult of ongoing exertion; is not substantially alleviated by rest; andresults in substantial reduction in previous levels ofoccupational, educational, social, or personalactivities.

Four or more of the following symptoms are concurrently present for more than 6 months:

• Impaired memory or concentration

•   Multijoint pain

•   Muscle pain

•   New headaches

•   Postexertional malaise

•   Sore throat

•   Tender cervical or axillary lymph nodes

•   Unrefreshing sleep

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 can 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

Adapted from Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Intern Med   1994;121:953–959.

Because some immune abnormalities are often seen in these patients, some people have called this “chronic fatigue and immune dysregulation syndrome.” The immune abnormalities seen in CFS patients are mild and differ from patient to patient. Most significantly, these patients are not immunosuppressed.

It has been noted that many of the symptoms of fibromyalgia overlap with CFS, and some clinicians consider fibromyalgia and CFS to be different aspects of the same disease because both often include pain and fatigue. These different names for the same syndrome can be confusing to patients and clinicians, and when managing patients with CFS it is important to explain this to them.

Epidemiology

Though chronic fatigue is an extremely common symptom, CFS is not. The former has been noted to have a prevalence of 10% to 25% in a number of studies. However, the point prevalence of CFS has been estimated to be in the range of 0.1%. CFS is overrepresented in young and middle-aged women, but it has been described in men and women and in all age groups.

Pathophysiology

The cause of CFS is unknown. Much effort has gone into trying to discern an infectious, endocrine, immune, or psychiatric cause, but to date none has been proved. Studies have shown a link between CFS and the presence of certain genes that mediate immune and stress responses. The findings suggest that difficulty managing stress may be linked to the development of CFS. They also suggest that there is not a single cause of CFS, but that there may be a number of stress- related triggers (physical or emotional) in those with a genetic predisposition. This is consistent with the typical course, in which a previously healthy person develops an acute illness that resolves but initiates CFS.

In March 2015 the Institute of Medicine (IOM) issued a 300-page review of the topic. As a result of this review they proposed a name change to Systemic Exertion Intolerance Disease (SEID). This comprehensive report has three major themes: 1. CFS has acquired a great deal of negative connotation with associated misunderstanding and prejudice. The name change to SEID is an attempt to disconnect this disease from past misunderstandings. 2. The criteria for diagnosis were greatly simplified with emphasis on the major features. (Box 2) 3. By using the term “disease” and with the ample reference support in the document the IOM unequivocally underscores the very real nature of this malady. The IOM report is too recent to know at this time whether it will be universally adopted, but it by far the most thorough examination of the topic.

Box 2
New Proposed Criteria for  CFS/SEID
Diagnosis requires that the patient have the following three symptoms:

•   A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest.

•   Post-exertional malaise

•   Unrefreshing sleep

At least one of the two following manifestations is also required:

•   Cognitive impairment

•   Orthostatic intolerance

Clinical Features and Diagnosis

Though there is, as yet, no diagnostic test, the history, physical examination, and laboratory testing are generally very characteristic and allow a clinician to confidently make the diagnosis. The typical story is one of a previously highly functioning person who develops an acute illness or other stressor. The acute problem resolves, but from that time on symptoms of CFS are triggered. Despite often profound symptoms, physical examination is persistently normal, as is laboratory testing. Symptoms are exacerbated by physical activity.

The pre-CFS medical history of the patient is not one of multiple medical problems. Affected patients are typically highly functioning persons who are struck down with this disease. Diagnostic features to emphasize in addition to the case definition noted in Box 1 include those noted in Box 3.

Box 3
Frequent features of Chronic Fatigue Syndrome
• Sudden onset of fatigue after a relatively common illness or other stressor

•   Previously active and healthy person

•   Symptoms very sensitive to exacerbation by physical activity

•   Normal physical examination and laboratory testing

•   Altered sleep

•   “Foggy” thought processes

• Lack of progression to organ failure or any significant objective organ abnormality

•   Joint and muscle aching without physical evidence of inflammation

•   Feverish feeling (sustained elevated temperatures [> 37.4°C] should prompt a search for an alternative diagnosis, because the CFS patient is not truly febrile)

• Diffuse aching that is not well localized to joints or muscles, but without erythema, effusion, or limitation of motion

• Muscles that are easily fatigued (however, strength is normal, and biopsies and electromyograms are also normal)

• Occasional mild cervical and/or axillary lymphadenitis (painful lymph nodes [lymphadenia] are a common complaint, but this is not a true lymphadenopathy)

In a patient with a typical story and examination, laboratory testing should be limited (Box 4). Testing for diseases with a low pretest likelihood runs the serious risk of false-positive results. This can result in further testing, diagnostic confusion, and unnecessary treatments.

Specifically, the signs and symptoms of CFS are not those of systemic lupus, Lyme disease, cytomegalovirus, bartonellosis, ehrlichiosis, or babesiosis. Serologic testing for these diagnoses is not helpful and can be harmful if the presence of antibodies results in the initiation of unwarranted medications. For similar reasons, neuroimaging without objective clinical findings is not indicated. Though abnormalities can be found, they are nonspecific and of no clinical utility. Tilt-table testing seems to be abnormal in many patients with CFS; however, testing is expensive and uncomfortable, and abnormal results do not alter management. Of course, if history, physical examination, and initial laboratory testing do reveal abnormalities, further laboratory evaluation should be undertaken to elucidate the cause of the aberration(s).

Box 4
Diagnostic Testing
Tests to Perform

•   Complete blood count

•   Comprehensive chemistry screen

•   Thyroid-stimulating hormone

•   Additional testing only with specific clinical indications

Do Not Routinely Do

•   ANA

•   Serology for CMV, EBV, Bartonella, Babesia, Ehrlichia, Anaplasma

•   MRI, SPECT or PET scans

•   Tilt table testing

Abbreviations: ANA = antinuclear antibody test; CMV = cytomegalovirus; EBV = Epstein–Barr virus; MRI = magnetic resonance imaging; PET = positron emission tomography; SPECT = single-photon–emission computed tomography.

 

Treatment

There is no established cure for CFS, but patients should be counseled that a number of things can be done to manage this often disabling illness (Box 5). These can be divided into things the clinician should do and things the patient should do.

Box 5
Therapy of Chronic Fatigue  Syndrome
Educate the patient and his or her support system about the diagnosis of chronic fatigue syndrome. Emphasize the validity of the diagnosis and of the patient’s symptoms. Make sure that there is an understanding about expectations.

• Aggressively manage specific symptoms of sleep disturbance, pain, and depression.

•   Consider cognitive behavioral therapy.

• Emphasize the need for gradual, graded exercise. Give the patient a specific “prescription” for this.

• Avoid the temptation to prescribe antimicrobials, corticosteroids, or other medications with no proven benefit and the potential to do harm.

• Discuss the pros and cons of using unstudied, expensive, or potentially dangerous “alternative therapies.”

Things the Clinician Should Do

To successfully manage CFS, a clinician must believe that the patient is truly symptomatic. Patients with CFS are not malingering. Because they often appear well and have consistently normal objective testing, they often become very defensive about their limitations. They are sensitive to the validity of their symptoms. Not only are they suffering but also they are blamed for it. Many patients with CFS are partially or totally disabled. Their outward healthy appearance belies the internal sense of ill health. It is common for relatives and colleagues to believe they are malingering. A vicious cycle of frustration, anger, and depression commonly ensues.

As part of establishing the validity of the diagnosis a clinician should review the history of CFS, emphasizing that this is not a new disease but was originally described centuries ago.

For successful management a clinician should give the patient enough time, specifically inquire about other diagnoses the patient is concerned about, and explain why they are not correct. The clinician should see the patient at regular intervals.

Make sure that the patient has reasonable expectations. Most patients with CFS have not had previous chronic illnesses or significant prolonged limitations. It is often necessary review the information about CFS with the patient’s family and to emphasize that this disabling illness is not volitional.

Though it is generally wise to avoid a discussion about whether the origin of CFS is psychiatric or organic, depression is an expected consequence of any chronic illness. Depression has specific treatments, and it should be aggressively diagnosed and treated. The patient should be told that successful management of depression will help him or her cope with CFS.

If a sleep disturbance exists that should also be aggressively managed, if necessary by a sleep specialist. Sleep deprivation makes other symptoms more difficult to deal with.

Chronic pain is very enervating. If pain is prominent, that should also be aggressively managed, often by a pain specialist.

It is important for the clinician to be cautious about ascribing all of a patient’s symptoms to CFS. Such patients are, of course, not protected from getting additional illnesses. Each symptom should be considered on its own before defaulting it to CFS.

Complementary therapies must be discussed or the patient might get the impression that the clinician is not comfortable in considering them; that can partially undermine the clinician–patient relationship.

Though all are of unproved benefit or risk, “complementary” therapies that are not dangerous, such as acupuncture, or expensive are reasonable to consider.

Things the Patient Should Do

Of the 350 studies that have looked at treatment options for CFS only cognitive behavioral therapy and graded exercise therapy have been shown to be of benefit. In cognitive behavioral therapy, the patient undergoes a series of 1-hour sessions designed to alter beliefs and behaviors that might delay recovery. Although exercise can exacerbate symptoms, deconditioning will also do so. Limiting activity can worsen weakness and depression. Thus, increased rest is not recommended and should be strongly discouraged. The risk of exacerbating symptoms can be reduced by cautiously setting less- ambitious exercise goals. Because many patients with CFS were particularly active before the onset of their illness and are impatient to get their former lives back, they often need strict guidelines to try to prevent overdoing exercise while at the same time getting a clear prescription to exercise. The exercise prescription should be individualized based on the degree of impairment, but it is wise to initially set goals on the low side to avoid exacerbating symptoms.

As part of the management of CFS patients, their families and, when appropriate, their employers need to reframe their expectations. CFS patients have a chronic, disabling illness. Families and others need to come to some understanding that patients cannot do all that they were able to do before the onset of CFS and that patients cannot “will” the disease away any more than they could will away a more visible disability.

Things that Should Not Be Done

There are many suggested remedies for CFS. Most are either unstudied or disproved. In particular, treatments that are expensive or potentially harmful should be avoided. There is no role for antimicrobial therapy. There is no role for antiviral therapy, including treatment for retroviruses. There is no role for intravenous immunoglobulin, corticosteroids, special diets, or vitamin treatments.

Prognosis

The likelihood for complete recovery from CFS is only fair. The disease tends to wax and wane over time, but in only a minority of patients does it completely resolve. If sustained improvement occurs it is generally over several years. Several features have been associated with a poorer prognosis, including age older than 38 years, more than eight symptoms, duration over 1.5 years, less than 16 years of formal education, a history of a dysthymic disorder, and a sustained belief that the disease is due to a physical cause.

Monitoring

Despite the lack of very effective treatment, many patients benefit from regular monitoring of their condition. Knowing they have scheduled visits minimizes the number of crises and emergency visits and allows the patient to reconnect with a validating physician.

Follow-up on a quarterly basis is a reasonable interval.

References

1.     Aronowitz R.A. From myalgic encephalitis to yuppie flu: A history of chronic fatigue syndromes. In: Rosenberg C.E., Golden J., eds. Framing Disease. New Brunswick, NJ: Rutgers University Press; 1992.

2.    Clark M.R., Katon W., Russo J., et al. Chronic fatigue: Risk factors for symptom persistence in a 2{1/2}-year follow-up study. Am J Med. 1995;98:187–195.

3.     Fulcher K.Y., White P.D. Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ. 1997;314:1647–1652.

4.    Goertzel B.N., Pennachin C., de Souza Coelho L., et al. Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome. Pharmacogenomics. 2006;7:475–483.

5.     Goldenberg D.L., Simms R.W., Geiger A., et al. High frequency of fibromyalgia in patients with chronic fatigue seen in a primary care practice. Arthritis Rheum. 1990;33:381–387.

6.      Institute of Medicine. Beyond myalgic encephalitis/chronic fatigue syndrome: redefining an illness. Washington D.C.: National Acdemies Press, 2015.

7.    Lightfoot Jr. R.W., Luft B.J., Rahn D.W., et al. Empiric parenteral antibiotic treatment of patients with fibromyalgia and fatigue and a positive serologic result for Lyme disease. A cost- effectiveness analysis. Ann Intern Med. 1993;119:503–509.

8.    Schluederberg A., Straus S.E., Peterson P., et al. NIH conference. Chronic fatigue syndrome research. Definition and medical outcome assessment. Ann Intern Med. 1992;117:325–331.

9.       Schwartz R.B., Garada B.M., Komaroff A.L., et al. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: Comparison of MR imaging and SPECT. Am J Roentgenol. 1994;162:935–941.

10.       Simmons G., Glynn S.A., Komaroff A.L., et al. Failure to confirm XMRV/MLVs in the blood of patients with chronic fatigue syndrome: A multi-laboratory study. Science. 2011;334:814– 817.

11.     Wessely S., Chalder T., Hirsch S., et al. The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: A prospective primary care study. Am J Public Health. 1997;87:1449–1455.

12.     White P.D., Goldsmith K.A., Johnson A.L., et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): A randomised trial. Lancet. 2011;377:823–836.

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