Stanley M. Bierman M.D., F.A.C.P. (C2003)

A Confusing, Misunderstood Disease Looking For Both A Cause and Cure.

Post-viral "poop", a near universal affliction of humankind, is characterized by temporary fatigue and exhaustion appearing in the wake of a number of well-defined acute viral diseases. Chronic fatigue accounts for 10-15 million office visits per year to physicians in the United States. The illness is controversial because no causal agent or diagnostic laboratory test has been identified.

Happily, patient complaints of easy fatigability and malaise are transient as they recover from the disabling infective grips of influenza, shingles or mononucleosis. There is, however, a subset of patients in whom, following a vague viral disorder, the degree of fatigue is excessive and persistent, and associated with profound weariness on minimal exertion. For these individuals, fatigue is seemingly an unending event, and comes to be both a physically debilitating and emotionally crippling encounter for the afflicted patient. Described initially under the euphemism of "nervous exhaustion" and then the scientific rubric of Neurasthenia, later designated as Acute Infective Encephalomyelitis, Neurocirculatory Asthenia, Post viral Syndrome, Chronic Mononucleosis, Chronic Epstein-Barr virus, most Americans have come to know this condition by the appellation of Chronic Fatigue Syndrome (CFS) or Yuppie Flu.

The recent interest in CFS appears to have grown out of reports from Nevada and reviewed by G.P. Holmes, M.D. (JAMA 1987; 257:2297-2302) which documented a peculiar post-viral flu-like disorder in which the most significant complaint was that of fatigue. The condition, which appeared in epidemic proportion in previously healthy individuals, was associated with a constellation of signs and symptoms including sore throat, unexplained low-grade fever, muscle pains and enlarged lymph nodes.

So profound and persistent are the complaints of fatigue that many patients with CFS find themselves unable to work. In some instances they become homebound, and a few reluctantly turn to Social Security Disability following a lifetime of productive work. This is all the more emotionally disabling given that patients with CFS are often well-educated, high-achievers in the 20 to 50 year age range who have been accustomed to hard work during their career development. Regrettably, some patients suffering from CFS have been stigmatized by claims from unsympathetic spouses or family that they are just lazy or malingerers, and criticized that it is "all in your head." A few patients have been dismissed by unknowing physicians with the glib admonition that they are merely experiencing a depressive episode during middle life crisis.

According to recent epidemiologic studies, one in five patients seen in general medical practice report varying degrees of chronic fatigue. Despite the prevalence of this complaint, it is disappointing to note that some members of the medical community deny that CFS exists as a distinct clinical entity. The problem of classification has been made all the more difficult because the etiologic or causative agent of the disorder has not been isolated.

To more carefully define the condition, G.P. Holmes of the Centers for Disease Control (CDC) has established a working definition of CFS. The two major criteria necessary to establish a diagnosis of CFS are: (1) relapsing fatigue or easy fatigability not resolved by bed rest, and severe enough to reduce average daily activity by more than 50% for at least six months; and (2) the exclusion of other clinical conditions, including psychiatric disorders to account for the complaint. In addition, there must be at least six other minor symptomatic criteria including: (1) unexplained low-grade fever or chills; (2) sore throat; (3) enlarged anterior or posterior cervical or axillary lymph nodes; (3) unexplained general muscle weakness; (4) muscle aches; (5) prolonged fatigue following exercise; (6) unaccustomed headaches; (7) migratory, noninflammatory joint pains; (8) sleep disturbances; (9) acute onset of symptoms of fatigue; and finally, (10) a constellation of neuropsychiatric problems including: (a) forgetfulness; (b) confusion; (c) inability to concentrate; (d) excess irritability; (e) difficulty in thinking; (f) depression; and (g) excess visual sensitivity to light. Finally, physical criteria must be documented by a physician on two separate occasions one month apart consisting of: (1) low-grade fever; (2) pharyngitis (sore throat); and (3) enlarged or tender neck or axillary lymph nodes. Additional signs and symptoms of CFS include anxiety, suicidal ideation, dizziness, stiffness, nausea, rapid heart rate, upset stomach, disturbance in sexual function, night sweats, and significant weight loss or gain.

If a total of two major and six minor criteria from the above list are established, the patient is deemed to have Chronic Fatigue Syndrome. While the Holmes criteria are restrictive, it is not uncommon to see patients who experience many of the subjective complaints, while lacking the objective symptoms of recurrent fever and sore throat. To distinguish and classify this group it is necessary for physicians to exclude other medical reasons for the patient's complaints before burdening the individual with a diagnosis of CFS.

Included in a broad list of alternative causes of chronic fatigue are endocrine disorders such as: (1-2) over or under activity of the thyroid; (3-4) over or under activity of the adrenal gland; and (5) sugar diabetes . There are rheumatologic disorders including: (1) fibromyalgia; (2) Sjogren's syndrome; (3) polymyalgia rheumatica; and (4) dermatomyositis. Infectious disorders may have fatigue as a central complaint and include: (1) chronic Epstein-Barr virus infection (mononucleosis); (2) influenza; (3) Human Immunodeficiency Virus; (4) brucellosis; (5) tuberculosis; and (6) Lyme disease.

Neuropsychiatric disorders are often associated with fatigue and include: (1) obstructive sleep syndromes; (2) multiple sclerosis; (3) affective disorders including depression: (4) hypochondriasis; and (5) somatization disorders. There are diseases of the blood such as anemia, or malignancies that can present with symptoms of fatigue including: (1) various types of leukemia; (2) lymphoma; and (3) occult or hidden malignancies. Finally the differential diagnosis for fatigue should include investigation of: (1) chronic illness or disorders of the kidneys, liver and lungs; (2) side effects of drugs such as tranquilizers; (3) alcohol or substance abuse; and (4) heavy-metal toxicity.

As noted in the introduction to this subject, despite unsuccessful attempts to elucidate the precise cause of Chronic Fatigue Syndrome (CFS), there is no lack of theories as to etiology. Well-defined infectious bacterial agents including brucella, tuberculosis, spirochetes including Borrelia burgdorferi (the causative agent of Lyme disease), along with entero and retroviruses and herpes type 6 virus, as well as Candida albicans, a fungal infection, have all been suspected of playing a role in this disease.

Of all the infectious agents incriminated in causation of CFS the Epstein-Barr virus (EBV), the etiologic or causative agent of mononucleosis, has received the most attention given the clinical similarity to CFS. A ubiquitous herpes virus, high titers of antibodies against EBV viral capsid antigen have been noted that some 95% of patients with CFS. There are conflicting studies suggesting that early antigens to EBV are (Ann Int Med 1985;102:1-7), and then are not (JAMA 1988; 260:971-73), helpful markers in establishing a diagnosis of CFS.

In the United Kingdom, enteroviruses, a category of picornaviruses, have been promoted as the etiologic agent of CFS, while other studies utilizing sophisticated polymerase chain reaction and Western blot techniques have proposed the human T-cell leukemia virus as a possible pathogen. Another unfounded theory proposes that sensitivity to mercury in dental amalgams may serve to trigger the disease.

A number of immunologic abnormalities have been described in patients with CFS including: (1) elevated titers of antibodies against EBV; (2) elevated or decreased gamma globulin levels; (3) increased or decreased interleukin-2; (4) increased helper/suppressor T-cell ratio; (5) increased or decreased natural killer cell activity; (6) presence of antinuclear antibodies (ANA). The trouble with these immunologic markers is that there is no clear correlation between the degree of abnormality and the severity of symptoms, nor are the immunologic findings consistent from time to time in the same patient.

One theory linking immunologic abnormalities to the development of CFS proposes that patients may have an immune system that overreacts to environmental or infectious antigens. Alternatively, patients may have inherited an immunoregulatory system that fails to shut off when the infectious insult has terminated. Another interesting observation is the high incidence of atopic disorders such as eczema, asthma and hay fever in individuals with CFS.

Recent advances in cytokine research have provided valuable insights in the pathogenesis of CFS. Cytokines are chemical messengers elaborated by T cell lymphocytes that function in controlling and directing host defense against pathogens. It is known that administration of interleukin-1 (IL-1) to healthy patients can produce symptoms of fever, fatigue, muscle aches and memory problems. Another intriguing observation is that the administration of the drug alpha-interferon is able to replicate many of the symptoms encountered by the patient with CFS. Another theory proposes that patients with CFS may have a genetic tendency to the disease analogous to that experienced by some patients with rheumatic disorders in which there is a special predisposition based on select HLA genotypes (i.e. B27 in ankylosis spondylitis).

Other investigations have been directed towards the possibility of a defect in down regulation of the hypothalamic-pituitary-adrenal axis in patients with CFS. Up regulation of hypothalamic serotonin receptors has also been reported in CFS. Likewise there have been abnormalities described on MRI scans and hypo perfusion of select portions of the brain demonstrated on SPECT and PET scans. It is intriguing to note that genes encoding brain receptors for neurotransmitters such as dopamine have multiple alleles.

Psychological explanations of CFS are high in a hierarchy of medical justifications used to dismiss the syndrome as a distinct clinical entity. Given that there is no simple laboratory basis for diagnosis, patients are sometimes spurned as being psychoneurotic. There is little doubt that patients with endogenous or reactive depression also may have complaints of profound fatigue. It has also been shown that half of patients with CFS have experienced an antecedent episode of major depression. Likewise recovery from CFS seems to be longer in patient with significant depression. The latter observation may relate to the fact that a number of neurohumoral and immunologic abnormalities have been documented in patients with chronic depression that parallel the depression of immune surveillance found in patients with CFS.

One of the most vexing aspects confronting patients with Chronic Fatigue Syndrome must surely lie in the multiplicity of purported approaches to management. Proposed treatments may vary from benign neglect to dubious interventions such as hypervitamin therapy with liver and B12 shots, or holistic approaches with herbs and acupuncture. There are reports that gamma globulin injection, high-dose essential fatty acid, magnesium sulfate, mood elevators have proven to be meritorious. The limiting factor in documenting efficacy relate to the absence of controls, the failure to acknowledge a placebo effect, and the short duration of treatment, making it difficult to gage response. It is important to note that patients with CFS often experience a variable clinical course with unpredictable exacerbations and remissions.

As but one example of the difficulty in establishing meaningful therapy, a 1986 study in Journal of Infectious Disease (IBID 1986;153:283-89) documented the beneficial clinical influence of acyclovir (Zovirax) in CFS, while a subsequent report in New England Journal of Medicine (IBID 1988;319:1692-98) found the drug to be without therapeutic benefit notwithstanding the potential benefit of high dose acyclovir in infectious mononucleosis.

There have been other treatment modalities suggested including the administration of anti-depressants as proposed by Goodnick and Sandoval (J Clin Psych 54:1 (Jan) 1993. Tricyclic anti-depressants such as amitryptyline 25 to 50mgm at bedtime on a six week trial have proven beneficial for both CFS and fibromyalgia.

In my experience the most predictable and sustained benefits of therapy for CFS have come from the intermittent administration of dexamethasone in doses of 0.75mgm twice daily for six days. Patients seem to experience a rapid resolution of their symptoms of fatigue which may be attributable to the influence of the steroid on either the immunologic arm of the disease, or its influence on the hypothalamic-pituitary axis. An alternative treatment consists of a one month reprieve of symptoms following a single injection of Kenalog 40mgm intramuscularly. Concerns by some physicians over immune suppression from steroids have not proven to be worrisome given the intermittent nature of treatment and cumulative low dose used.

On empiric grounds, I have administered second generation antiviral agents such as Valtrex and Famvir on a short-term basis. In one study over 50 percent of patients improved over time without any therapeutic intervention (JAMA 264:48 (July 4) 1990.

In conclusion, the physician's personal approach to individuals with CFS should include educational enlightenment, along with strong emotional support and understanding. Patients should receive instruction into a good diet, encouraged to have a good night's sleep, and advised to relax both their mind and body through meditation techniques. It is increasingly clear that psychological factors contribute to patients' vulnerability and recovery from infection. Significant reduction in stress, depression and other negative mood states correlates with overall clinical improvement. Thus a patient's expectation from treatment and the physician's positive attitude are important elements in the complex equation governing recovery from infection.

Information for patients: Center for Disease Control and Prevention CFS phone (888)232-3228

After connecting to this number, on a touch phone press 2-2-1-3-6-1 and you will be forwarded to the CFS information system.
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