Chronic Fatigue Syndrome (CFS)

What is CFS?

Chronic fatigue syndrome, or CFS, is a debilitating and complex disorder characterised by profound fatigue that is not improved by bed rest and that may be worsened by physical or mental activity. Persons with CFS most often function at a substantially lower level of activity than they were capable of before the onset of illness. In addition to these key defining characteristics, patients report various nonspecific symptoms, including weakness, muscle pain, impaired memory and/or mental concentration, insomnia, and post-exertional fatigue lasting more than 24 hours. In some cases, CFS can persist for years. The cause or causes of CFS have not been identified and no specific diagnostic tests are available. Moreover, since many illnesses have incapacitating fatigue as a symptom, care must be taken to exclude other known and often treatable conditions before a diagnosis of CFS is made.

Definition of CFS

A great deal of debate has surrounded the issue of how best to define CFS. In an effort to resolve these issues, an international panel of CFS research experts convened in 1994 to draft a definition of CFS that would be useful both to researchers studying the illness and to clinicians diagnosing it. In essence, in order to receive a diagnosis of chronic fatigue syndrome, a patient must satisfy two criteria:

  1. Have severe chronic fatigue of six months or longer duration with other known medical conditions excluded by clinical diagnosis; and
  2. Concurrently have four or more of the following symptoms: substantial impairment in short-term memory or concentration; sore throat; tender lymph nodes; muscle pain; multi-joint pain without swelling or redness; headaches of a new type, pattern or severity; unrefreshing sleep; and post-exertional malaise lasting more than 24 hours.

The symptoms must have persisted or recurred during six or more consecutive months of illness and must not have predated the fatigue.

Similar Medical Conditions

A number of illnesses have been described that have a similar spectrum of symptoms to CFS. These include fibromyalgia syndrome, myalgic encephalomyelitis, neurasthenia, multiple chemical sensitivities, and chronic mononucleosis. Although these illnesses may present with a primary symptom other than fatigue, chronic fatigue is commonly associated with all of them.

Other Conditions That May Cause Similar Symptoms

In addition, there are a large number of clinically defined, frequently treatable illnesses that can result in fatigue. Diagnosis of any of these conditions would exclude a definition of CFS unless the condition has been treated sufficiently and no longer explains the fatigue and other symptoms. These include hypothyroidism, sleep apnoea and narcolepsy, major depressive disorders, chronic mononucleosis, bipolar affective disorders, schizophrenia, eating disorders, cancer, autoimmune disease, hormonal disorders

  • , subacute infections, obesity, alcohol or substance abuse, and reactions to prescribed medications.
    • Other Commonly Observed Symptoms in CFS

    In addition to the eight primary defining symptoms of CFS, a number of other symptoms have been reported by some CFS patients. The frequencies of occurrence of these symptoms vary from 20% to 50% among CFS patients. They include abdominal pain, alcohol intolerance, bloating, chest pain, chronic cough, diarrhoea, dizziness, dry eyes or mouth, earaches, irregular heartbeat, jaw pain, morning stiffness, nausea, night sweats, psychological problems (depression, irritability, anxiety, panic attacks), shortness of breath, skin sensations, tingling sensations, and weight loss.

    Possible Causes of CFS

    The cause or causes of CFS remain unknown, despite a vigorous search. While a single cause for CFS may yet be identified, another possibility is that CFS represents a common endpoint of disease resulting from multiple precipitating causes. As such, it should not be assumed that any of the possible causes listed below has been formally excluded, or that these largely unrelated possible causes are mutually exclusive. Conditions that have been proposed to trigger the development of CFS include virus infection or other transient traumatic conditions, stress, and toxins.

    Infectious Agents

    Due in part to its similarity to chronic mononucleosis, CFS was initially thought to be caused by a virus infection, most probably Epstein-Barr virus (EBV). It now seems clear that CFS cannot be caused exclusively by EBV or by any single recognised infectious disease agent. No firm association between infection with any known human pathogen and CFS has been established. CDC's four-city surveillance study found no association between CFS and infection by a wide variety of human pathogens, including EBV, human retroviruses, human herpesvirus 6, enteroviruses, rubella, Candida albicans, and more recently bornaviruses and Mycoplasma. Taken together, these studies suggest that among identified human pathogens, there appears to be no causal relationship for CFS. However, the possibility remains that CFS may have multiple causes leading to a common endpoint, in which case some viruses or other infectious agents might have a contributory role for a subset of CFS cases.

    Immunology

    It has been proposed that CFS may be caused by an immunologic dysfunction, for example inappropriate production of cytokines, such as interleukin-1, or altered capacity of certain immune functions. One thing is certain at this juncture: there are no immune disorders in CFS patients on the scale traditionally associated with disease. Some investigators have observed anti-self antibodies and immune complexes in many CFS patients, both of which are hallmarks of autoimmune disease. However, no associated tissue damage typical of autoimmune disease has been described in patients with CFS. The opportunistic infections or increased risk for cancer observed in persons with immunodeficiency diseases or in immunosuppressed individuals is also not observed in CFS. Several investigators have reported lower numbers of natural killer cells or decreased natural killer cell activity among CFS patients compared with healthy controls, but others have found no differences between patients and controls.

    T-cell activation markers have also been reported to have differential expression in groups of CFS patients compared with controls, but again, not all investigators have consistently observed these differences. One intriguing hypothesis is that various triggering events, such as stress or a viral infection, may lead to the chronic expression of cytokines and then to CFS. Administration of some cytokines in therapeutic doses is known to cause fatigue, but no characteristic pattern of chronic cytokine secretion has ever been identified in CFS patients. In addition, some investigators have noted clinical improvement in patients with continued high levels of circulating cytokines; if a causal relationship exists between cytokines and CFS, it is likely to be complex. Finally, several studies have shown that CFS patients are more likely to have a history of allergies than are healthy controls. Allergy could be one predisposing factor for CFS, but it cannot be the only one, since not all CFS patients have it.

    Hypothalamic-Pituitary Adrenal (HPA) Axis

    Multiple laboratory studies have suggested that the central nervous system may have an important role in CFS. Physical or emotional stress, which is commonly reported as a pre-onset condition in CFS patients, activates the hypothalamic-pituitary-adrenal axis, or HPA axis, leading to increased release of cortisol and other hormones. Cortisol and corticotrophin-releasing hormone (CRH), which are also produced during the activation of the HPA axis, influence the immune system and many other body systems. They may also affect several aspects of behaviour. Recent studies revealed that CFS patients often produce lower levels of cortisol than do healthy controls. Similar hormonal abnormalities have been observed by others in CFS patients and in persons with related disorders like fibromyalgia. Cortisol suppresses inflammation and cellular immune activation, and reduced levels might relax constraints on inflammatory processes and immune cell activation. As with the immunologic data, the altered cortisol levels noted in CFS cases fall within the accepted range of normal, and only the average between cases and controls allows the distinction to be made. Therefore, cortisol levels cannot be used as a diagnostic marker for an individual with CFS. A placebo-controlled trial, in which 70 CFS patients were randomized to receive either just enough hydrocortisone each day to restore their cortisol levels to normal or placebo pills for 12 weeks, concluded that low levels of cortisol itself are not directly responsible for symptoms of CFS, and that hormonal replacement is not an effective treatment. However, additional research into other aspects of neuroendocrine correlates of CFS is necessary to fully define this important, and largely unexplored, field.

    Neurally Mediated Hypotension

    Rowe and coworkers conducted studies to determine whether disturbances in the autonomic regulation of blood pressure and pulse (neurally mediated hypotension, or NMH) were common in CFS patients. The investigators were alerted to this possibility when they noticed an overlap between their patients with CFS and those who had NMH. NMH can be induced by using tilt table testing, which involves laying the patient horizontally on a table and then tilting the table upright to 70 degrees for 45 minutes while monitoring blood pressure and heart rate. Persons with NMH will develop lowered blood pressure under these conditions, as well as other characteristic symptoms, such as lightheadedness, visual dimming, or a slow response to verbal stimuli. Many CFS patients experience lightheadedness or worsened fatigue when they stand for prolonged periods or when in warm places, such as in a hot shower. These conditions are also known to trigger NMH. One study observed that 96% of adults with a clinical diagnosis of CFS developed hypotension during tilt table testing, compared with 29% of healthy controls. Tilt table testing also provoked characteristic CFS symptoms in the patients. A study (not placebo-controlled) was conducted to determine whether medications effective for the treatment of NMH would benefit CFS patients. A subset of CFS patients reported a striking improvement in symptoms, but not all patients improved. A placebo-controlled trial of NMH medications for CFS patients is now in progress.

    Nutritional Deficiency

    There is no published scientific evidence that CFS is caused by a nutritional deficiency. Many patients do report intolerances for certain substances that may be found in foods or over-the-counter medications, such as alcohol or the artificial sweetener aspartame. While evidence is currently lacking for nutritional defects in CFS patients, it should also be added that a balanced diet can be conducive to better health in general and would be expected to have beneficial effects in any chronic illness.

    Treatment of Patients with Chronic Fatigue Syndrome

    A variety of therapeutic approaches have been described as benefiting patients with chronic fatigue syndrome (CFS). Since no cause for CFS has been identified and the pathophysiology remains unknown, treatment programs are directed at relief of symptoms, with the goal of the patient regaining some level of pre-existing function and well-being. Although desirable, a rapid return to pre-illness health may not be realistic, and patients who expect this prompt recovery and do not experience it may exacerbate their symptoms because of overexertion, become frustrated, and may become more refractory to rehabilitation.

    Decisions regarding treatment for CFS or any chronically fatiguing illness should be made only in consultation with a health care provider. The health care provider, together with the patient, will develop an individually tailored programme that provides the greatest benefit. This treatment programme will be based on assessment of the patient's overall medical condition and current symptoms, and will be modified over time on the basis of regular follow-up and assessment of the patient's changing condition. Currently, most health care providers with experience in treating persons with CFS use some combination of the therapies discussed below. Persons who have questions about a particular treatment should contact a qualified health care provider, local medical society, or university medical school for additional information.

    Some proposed treatments are unproven and may be harmful. Therapy should not aggravate existing symptoms or create new ones. It should not mask another illness that needs identification and specific treatment. Finally, therapy should not impose an excessive financial burden on the patient.

    As a service to CFS patients and other interested persons, this section provides some basic information about different therapies that have been used for the treatment of patients with CFS. These descriptions are intended only for general informational purposes. The Agency for Healthcare Research and Quality has recently completed an Evidence Report Defining and Managing Chronic Fatigue Syndrome that can be downloaded from their website.

    Non-Pharmacologic Therapy

    Physical Activity

    An appropriate amount of physical activity is required by everyone for physical and emotional well-being. Patients with CFS are no exception. A key consideration for patients with CFS is to know how much to do and when to stop the activity. Regardless of the level of activity a patient with CFS may attempt, the most important guideline is to avoid increasing the level of fatigue.

    In general, health care providers advise patients with CFS to pace themselves carefully and encourage them to avoid unusual physical or emotional stress. The paced activity can be counter-productive if it increases fatigue or pain. A regular, manageable daily routine helps avoid the "push-crash" phenomenon characterised by overexertion during periods of better health, followed by a relapse of symptoms perhaps initiated by the excessive activity. Although patients should be as active as possible, clinicians may need to explain the disorder to employers and family members, advising them to make allowances as possible. Modest regular exercise to avoid de-conditioning is important. The programme of exercise and/or the exercise itself should be supervised by a knowledgeable health care provider or physical therapist. Such supervision is particularly important for severely compromised patients.

    Non-pharmacologic therapies that have a passive physical component sometimes used by CFS patients include massage therapy, acupuncture, chiropractic, cranial-sacral, massage, self-hypnosis, and therapeutic touch. These modalities may contribute to feeling better, but they are most effective when combined with patient-generated activity, including aquatic therapy, light exercise (adapted to personal capabilities), and stretching. Some patients may tolerate activities such as yoga and tai chi that require more energy.

    Education

    Learning about what CFS is and what it is not is a critical component of therapy. This approach includes learning how to adjust activities and behaviours that may aggravate the illness. A formal method to impart this information is known as cognitive behavioural therapy. Cognitive behavioural therapy has been shown to facilitate patient coping and to allow increased activities without triggering increased symptoms. Any chronic illness, including CFS, can affect the patient's family. Family education may foster good communication and reduce the adverse effect of CFS on the family.

    Pharmacologic Therapy

    Pharmacologic therapy is directed toward the relief of specific symptoms experienced by the individual patient. Patients with CFS appear particularly sensitive to many medications, especially those that affect the central nervous system. Thus, the usual treatment strategy is to begin with very low doses and to gradually increase dosage as necessary and as tolerated. It is important to remember that use of any drug for symptom relief should be attempted only if an underlying cause for the symptom in question has not been found. The best example is use of a sleep-enhancing medication for non-restorative sleep. Although the patient may state that they sleep better, the sleep disorder remains obscured and thus treatment of the sleep disorder not given. It is also important to remember that all medications can cause untoward side effects, which may lead to new symptoms.

    Prescription Medications

    Nonsteroidal antiinflammatory drugs: These drugs can be used to relieve pain in CFS patients. Some are available as over-the-counter medications. Examples include naproxen (Aleve, Anaprox, Naprosen), ibuprofen (Advil, Bayer Select, Motrin, Nuprin), and piroxicam (Feldene). Prescription drugs include tramadol hydrochloride (Ultram), coelecoxib (Celebrex), and refecoxib (Vioxx). These medications are generally safe when used as directed, but can cause a variety of adverse effects, including kidney damage, gastrointestinal bleeding, abdominal pain, nausea, and vomiting. Some patients may become dependent on certain of these agents.

    Low-dose tricyclic antidepressants: Tricyclic agents may be prescribed for CFS patients to improve sleep and to relieve mild, generalised pain. Examples include doxepin (Adapin, Sinequan), amitriptyline (Elavil, Etrafon, Limbitrol, Triavil), desipramine (Norpramin), and nortriptyline (Pamelor). Effective dosages are often much lower than those used to treat depression. Some adverse reactions include dry mouth, drowsiness, weight gain, and elevated heart rate.

    Other antidepressants: Newer antidepressants have been used to treat depression in CFS patients, although non-depressed CFS patients receiving treatment with serotonin reuptake inhibitors have been found by some health care providers to benefit from this treatment as well or better than depressed patients. Examples of antidepressants used to treat patients with CFS include serotonin reuptake inhibitors, such as fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil); venlafaxine (Effexor); trazodone (Desyrel); and bupropion (Wellbutrin). A number of adverse reactions, varying with the specific drug, may be experienced, but include agitation, sleep disturbances, and increased fatigue.

    Anxiolytic agents: Anxiolytic agents may be used to treat symptoms of anxiety in CFS patients. Examples include alprazolam (Xanax) and lorazepam (Ativan). Clonazepam (Klonopin) is another member of this family of drugs that is used to control exaggerated nervous systems problems such as vertigo, burning or exaggerated tenderness in the skin, and "nervous" limb movements, may also be useful. However, they should not be used in the general treatment of CFS. Common adverse reactions include sedation, amnesia, and symptoms accompanying acute withdrawal (insomnia, abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions).

    Stimulants: Fatigue by itself is not a good indication for symptomatic therapy. However, if the fatigue represents lethargy or daytime sleepiness, treatment may be indicated. Trials of a wakefulness agent, modofanil (Provigil), have been completed, but the results have not yet been published. In a small group of patients with excessive sleepiness, the drug decreased symptoms compared with placebo. This drug is currently indicated only with the diagnoses of narcolepsy and excess daytime sleepiness when identified by the proper sleep studies.

    Antimicrobials: An infectious cause for CFS has not been identified, and antibiotics, antivirals, and antifungal agents should not be prescribed for treatment of CFS, unless the patient has been diagnosed with a concurrent infection. A controlled trial of the antiviral drug acyclovir found no benefit for the treatment of patients with CFS. Indiscriminate use of antimicrobials can have a myriad of adverse effects, including increasing the risk for resistant organisms.

    Anti-allergy therapy: Some CFS patients have histories of allergy, and these symptoms may flare periodically. Non-sedating antihistamines may be helpful for CFS patients with allergies. Examples include desloratadine (Clarinex), fexofenadine (Allegra), and ceterizine (Zyrtec). However, anti-allergy therapy has no efficacy in the treatment of CFS itself. Some of the more common adverse reactions associated with use of these medications include drowsiness, fatigue, and headache. Sedating antihistamines such as Benadryl can also be of benefit to patients at bedtime. The tricyclic antidepressants mentioned above also have potent antihistamine effects.

    Antihypotensive/antitachycardia therapy: CFS does not respond to treatment with antihypotensive or antitachycardic drugs and general use of such medications may be harmful. However, such medications may be useful in specific circumstances. For example, fludrocortisone (Florinef) has been prescribed for CFS patients who have had a positive tilt table test. However controlled studies have not found Florinef alone effective in the general treatment of CFS patients. Beta blockers such as atenolol (Tenormin) have also been prescribed for patients with orthostatic hypotension. Midodrine (Proamatine), an agent that directly increases blood pressure, may be useful in selected patients identified by an abnormal tilt test. Increased salt and water intake is also recommended for these patients but should be done only under supervision of a health care provider. Adverse reactions include elevated blood pressure and fluid retention.

    Experimental Drugs and Treatments

    Ampligen is a synthetic nucleic acid product that was designed to stimulate the production of interferons, a family of immune response modifiers that are also known to have antiviral activity. Although it may not directly induce interferon, reports of double-blinded, placebo-controlled studies of CFS patients documented modest improvements in cognition and performance among Ampligen recipients compared with the placebo group. These preliminary results will need to be confirmed by further study. The Food and Drug Administration (FDA) does not approve Ampligen for widespread use, and the administration of this drug in CFS patients should be considered experimental. Ampligen is not widely available, is costly, and is generally not reimbursable through insurance programs. Finally, although most recipients of Ampligen tolerated the drug well, adverse reactions, such as liver damage, were reported and are still incompletely characterised.

    Gamma globulin is pooled human immune globulin and contains antibody molecules directed against a broad range of common infectious agents. Gamma globulin is ordinarily used as a means for passively immunising persons whose immune system has been compromised, or who have been exposed to an agent that might cause more serious disease in the absence of immune globulin. Gamma globulin is not effective in the treatment of CFS. Serious adverse reactions are uncommon, although in rare instances gamma globulin may initiate anaphylactic shock.

    Corticosteroids. Controlled studies of corticosteroids have been conducted because some patients with CFS had a slight decrease in urinary cortisol levels. Some benefits were noted in patients treated with low dose hydrocortisone but the effects disappeared after one month. High dose replacement therapy had some benefit but was complicated by attendant adrenal suppression.

    Dehydroepiandrosterone (DHEA) was reported in preliminary studies to improve symptoms in some patients. However, in subsequent studies, this finding has not been confirmed and the use of DHEA in patients should be regarded as experimental. Its use should be limited to patients with documented abnormalities in DHEA levels and function.

    High colonic enemas have no demonstrated value in the treatment of CFS. The procedure can promote intestinal disease.

    Kutapressin is a crude extract from pig's liver. It is not readily available and there is no scientific evidence that it has any value in the treatment of CFS patients. Kutapressin can elicit allergic reactions.

    Neurosurgery. Unpublished reports of malformations at the base of the skull (Chiari malformations) as being causative of CFS have been circulated, and surgical intervention has been suggested in some of those unsubstantiated reports. Surgical intervention is not recommended at this time.

    Dietary Supplements and Herbal Preparations

    A variety of dietary supplements and herbal preparations are claimed to have potential benefits for CFS patients. With few exceptions, the effectiveness of these remedies for treating CFS has not been evaluated in controlled trials. Contrary to common belief, the "natural" origin of a product does not ensure safety. Dietary supplements and herbal preparations can have potentially serious side reactions and some can interfere or interact with prescription medications. CFS patients should seek the advice of their health care provider before using any unprescribed remedy.

    Vitamins, coenzymes, minerals: Preparations that have been claimed to have benefit for CFS patients include adenosine monophosphate, coenzyme Q-10, germanium, glutathione, iron, magnesium sulfate, melatonin, NADH, selenium, l-tryptophan, vitamins B12, C, and A, and zinc. An early CFS study found reduced red blood cell magnesium sulfate in CFS patients, but two subsequent studies have found no difference between patients and healthy controls. The therapeutic value of all these preparations for CFS has not been validated.

    Herbal preparations: Plants are known sources of many pharmacological materials. However, unrefined plant preparations contain variable levels of the active compound and may contain many irrelevant, potentially harmful substances. Preparations that have been claimed to have benefit to CFS patients include astralagus, borage seed oil, bromelain, comfrey, echinacea, garlic, Ginkgo biloba, ginseng, primrose oil, quercetin, St. John's wort, and Shiitake mushroom extract. Only primrose oil was evaluated in a controlled study, and the beneficial effects noted in CFS patients have not been independently confirmed. Some herbal preparations, notably comfrey and high-dose ginseng, have recognised harmful effects.

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