Pizzorno: Textbook of Natural Medicine, 2nd ed., Copyright © 1999 Churchill Livingstone, Inc.

Chapter 49 – Chronic fatigue syndrome

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Michael T. Murray ND
Joseph E. Pizzorno Jr ND
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DIAGNOSTIC SUMMARY
• Mild fever
• Recurrent sore throat
• Painful lymph nodes
• Muscle weakness
• Muscle pain
• Prolonged fatigue after exercise
• Recurrent headache
• Migratory joint pain
• Depression
• Sleep disturbance (hypersomnia or insomnia).
INTRODUCTION
The chronic fatigue syndrome (CFS) is a newly established syndrome that describes varying combinations of symptoms including recurrent fatigue, sore throats, low-grade fever, lymph node swelling, headache, muscle and joint pain, intestinal discomfort, emotional distress and/or depression, and loss of concentration.
Although newly defined and currently popular, CFS is not a new disease at all. References to a similar condition in the medical literature go back as far as the 1860s. In the past, chronic fatigue syndrome has been known by a variety of names including, among many others:
• chronic mononucleosis-like syndrome or chronic EBV syndrome
• Yuppie flu
• postviral fatigue syndrome
• post-infectious neuromyasthenia
• chronic fatigue and immune dysfunction syndrome (CFIDS)
• Iceland disease
• Royal Free Hospital disease.
In addition, symptoms of chronic fatigue syndrome mirror symptoms of neurasthenia, a condition first described in 1869.
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Definition
In response to the growing interest, chronic fatigue syndrome was formally defined in 1988 by a consensus panel convened by the Centers for Disease Control (CDC) in an attempt to establish a guide for evaluating patients with chronic fatigue of unknown cause by clinical physicians and researchers.[1]
A formal (and controversial) set of diagnostic criteria were established by the CDC (see Table 49.1 ). These criteria are controversial for many reasons including the fact that psychological symptoms are both a minor criterion and potential grounds for exclusion. One of the major complaints from physicians about the CDC definition is that it appears better suited for research than for clinical purposes. A major problem with the CDC criteria is that they ignore many of the common symptoms reported by patients with CFS (see Table 49.2 ).
The British and Australian criteria for the diagnosis of CFS are less strict than the CDC definition.[2] In particular, the minor diagnostic criteria are not required and the major diagnostic criteria are not as strict. For example, in the Australian definition the major criterion is simply fatigue at a level which causes disruption of daily activities in the absence of other medical conditions associated with fatigue.
Using the CDC criteria, the prevalence of CFS in individuals suffering from chronic fatigue in the United States is thought to be about 11.5%, using British criteria
TABLE 49-1 — CDC diagnostic criteria for chronic fatigue syndrome
Major criteria
• New onset of fatigue causing 50% reduction in activity for at least 6 months
• Exclusion of other illnesses that can cause fatigue
Minor criteria
• Presence of eight of the 11 symptoms listed below, or six of the 11 symptoms and two of the three signs
Symptoms
1. Mild fever
2. Recurrent sore throat
3. Painful lymph nodes
4. Muscle weakness
5. Muscle pain
6. Prolonged fatigue after exercise
7. Recurrent headache
8. Migratory joint pain
9. Neurological or psychological complaints
—sensitivity to bright light
—forgetfulness
—confusion
—inability to concentrate
—excessive irritability
—depression
10. Sleep disturbance (hypersomnia or insomnia)
11. Sudden onset of symptom complex
Signs
1. Low-grade fever
2. Non-exudative pharyngitis
3. Palpable or tender lymph nodes

TABLE 49-2 — Frequency of symptoms in CFS
Symptom/sign Frequency (%)
Fatigue 100
Low-grade fever 60–95
Muscle pain 20–95
Sleep disorder 15–90
Impaired mental function 50–85
Depression 70–85
Headache 35–85
Allergies 55–80
Sore throat 50–75
Anxiety 50–70
Muscle weakness 40–70
Post-exercise fatigue 50–60
Premenstrual syndrome (women) 50–60
Stiffness 50–60
Visual blurring 50–60
Nausea 50–60
Dizziness 30–50
Joint pain 40–50
Dry eyes and mouth 30–40
Diarrhea 30–40
Cough 30–40
Decreased appetite 30–40
Night sweats 30–40
Painful lymph nodes 30–40

it is about 15%, and using the Australian criteria it is about 38%. [2]
ETIOLOGY
Epstein–Barr virus
Many research studies have focused on identifying an infectious agent as the cause of CFS. The Epstein–Barr virus (EBV) emerged as the leading, yet controversial, candidate.[3] [4] [5] [6] [7] EBV is a member of the herpes group of viruses, which includes herpes simplex types 1 and 2, varicella zoster virus, cytomegalovirus, and pseudorabies virus. A common aspect of these viruses is their ability to establish a life-long latent infection after the initial infection. This latent infection is kept in check by a normal immune system. When the immune system is compromised in any way, these viruses can become active as viral replication and spread is increased. This is commonly observed with herpes virus infections, especially in immunocompromised individuals such as those with AIDS, cancer, or drug-induced immunosuppression.
Infection with EBV is inevitable among humans. By the end of early adulthood, almost all individuals demonstrate detectable antibodies in their blood to the Epstein–Barr virus, indicating past infection. When the primary infection occurs in childhood, there are usually no symptoms, but when it occurs in adolescence or early adulthood, the clinical manifestations of infectious mononucleosis develop in approximately 50% of the cases.
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Although reports of a prolonged or recurrent mononucleosis-like syndrome began appearing in the 1940s and 1950s, it wasn’t until the 1980s that evidence had implicated EBV in this broad clinical spectrum of chronic fatigue and associated symptoms. Numerous studies have now demonstrated persistently elevated titers (levels) of serum antibodies against the Epstein–Barr virus (specifically, anti-EBV capsid antibody titers > 1:80) in a number of patients presenting with the symptom pattern of this syndrome.
A careful study of 134 patients who had undergone EBV antibody testing because of suspected chronic mononucleosis-like syndrome found mixed results about the importance of EBV infection.[8] Fifteen patients identified as having severe, persistent fatigue of unknown origin were compared with the remaining 119 with less severe illness and with 30 age- and race-matched controls. The more seriously ill patients generally had higher levels of EBV antibodies than did the comparison groups, and, interestingly, they also demonstrated higher antibody titers to cytomegalovirus, herpes simplex viruses types 1 and 2, and measles. This led the researchers to conclude that “some patients with these illnesses (syndromes of chronic fatigue) may have an abnormality of infectious and/or immunologic origin”, and that there remain “questions concerning the relationship between CFS and EBV”.
Current knowledge about EBV infection can be summarized as follows:
• EBV and the herpes group of viruses produce latent life-long infections.
• The host’s immune system (T-lymphocytes, interferon, and other lymphokines) normally holds the latent infection in check.
• Any compromise in the immune system can lead to the reactivation of the virus and recurrent infection.
• The infection itself can compromise and/or disrupt immunity, thereby leading to other diseases.
• Elevated EBV antibody levels are observed in a significant number of diseases characterized by immunological dysfunction.
• Elevated antibody titers to the herpes group viruses, measles, and other viruses have also been observed in patients with chronic fatigue syndrome.
EBV antibody testing (and antibody testing for other herpes group viruses and measles) may be useful as a measure of immune function and overall host resistance, but should not be relied upon for diagnosis of CFS.
Other infectious agents
In addition to EBV, a number of other viruses have been investigated as possible causes of EBV. This search

TABLE 49-3 — Organisms proposed as causative agents in CFS
• Epstein–Barr virus
• Human herpes virus-6
• Inoue–Melnich virus
• Brucella
• Borrelia burgdorferi
• Giardia lamblia
• Cytomegalovirus
• Enterovirus
• Retrovirus

for a viral agent is consistent with the mainstream medical approach to focus on the infectious organism rather than on reducing susceptibility and supporting the individual’s immune system to deal with the organism effectively.[3] [4] [5] Table 49.3 lists the organisms currently proposed as causative agents in CFS.
Immune system abnormalities
There is little argument that a disturbed immune system plays a central role in CFS. A variety of immune system abnormalities have been reported in CFS patients (see Table 49.4 ). While no specific immunological dysfunction pattern has been recognized, the most consistent abnormality is a decreased number or activity of natural killer (NK) cells.[3] [4] [9] [10] NK cells received their name because of their ability to destroy cells that have become cancerous or infected with viruses. In fact, for a time, CFS was also referred to as low natural killer cell syndrome (LNKS).
Other consistent findings include a reduced ability of lymphocytes, key in the battle against viruses, to respond to stimuli.[10] One of the reasons for this lack of response may be a reduced activity or decreased production of interferon. While both low and high levels of interferon have been reported in CFS, levels are depressed in most cases. When interferon levels are low, reactivation of latent viral infection is likely. Conversely, when interferon (as well as other chemical mediators like interleukin-1) levels are high, many of the symptoms may be related to the physiological effects of interferon. When interferon is used as a therapy in cancer and viral hepatitis, the side-effects produced are quite similar to the symptoms of CFS.
TABLE 49-4 — Immunologic abnormalities reported for CFS
• Elevated levels of antibodies to viral proteins
• Decreased natural killer cell activity
• Low or elevated antibody levels
• Increased or decreased levels of circulating immune complexes
• Increased cytokine (e.g. interleukin-2) levels
• Increased or decreased interferon levels
• Altered helper/suppressor T-cell ratio

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Chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivities
Fibromyalgia (FM) and multiple chemical sensitivities (MCS), like CFS, are recently recognized disorders with a substantial overlap of symptomatology.[3] [4] [11] [12] The only difference in diagnostic criteria for fibromyalgia and CFS is the requirement of musculoskeletal pain in fibromyalgia and fatigue in CFS. The likelihood of being diagnosed as having fibromyalgia or CFS is dependent upon the type of physician consulted. Specifically, if a rheumatologist or orthopedic specialist is consulted, the patient is much more likely to be diagnosed with fibromyalgia ( Table 49.5 presents the diagnostic criteria for fibromyalgia).
One group of researchers carefully compared the symptomatology of 90 patients who had been diagnosed as having CFS, MCS or FM (30 in each category).[12] Utilizing the same questionnaire for all 90 patients, 70% of the patients diagnosed with FM and 30% with MCS met the Centers for Disease Control criteria for CFS. Particularly significant was the observation that 80% of both the FM and MCS patients met the CFS criteria of fatigue lasting more than 6 months with a 50% reduction in activity. More than 50% of the CFS and FM patients reported adverse reactions of various chemicals.
Other causes of chronic fatigue
Chronic fatigue can be caused by a variety of physical and psychological factors. Table 49.6 lists the major causes of chronic fatigue in an order of importance that is representative of how common the cause is among sufferers of chronic fatigue in the general population. The list is based on the findings of several large studies as well as the authors’ clinical experience (chronic fatigue syndrome is listed under a broader category of impaired immune function).
TABLE 49-5 — Diagnostic criteria for fibromyalgia. Diagnosis requires fulfillment of all three major criteria and four or more minor criteria
Major criteria
• Generalized aches or stiffness of at least three anatomic sites for at least 3 months
• Six or more typical, reproducible tender points
• Exclusion of other disorders which can cause similar symptoms
Minor criteria
• Generalized fatigue
• Chronic headache
• Sleep disturbance
• Neurological and psychological complaints
• Joint swelling
• Numbing or tingling sensations
• Irritable bowel syndrome
• Variation of symptoms in relation to activity, stress, and weather changes

TABLE 49-6 — Causes of chronic fatigue
• Pre-existing physical condition
—diabetes
—heart disease
—lung disease
—rheumatoid arthritis
—chronic inflammation
—chronic pain
—cancer
—liver disease
—multiple sclerosis
• Prescription drugs
—antihypertensives
—anti-inflammatory agents
—birth control pills
—antihistamines
—corticosteroids
—tranquilizers and sedatives
• Depression
• Stress/low adrenal function
• Impaired liver function and/or environmental illness
• Impaired immune function
—chronic fatigue syndrome
—chronic Candida infection
—other chronic infections
• Food allergies
• Hypothyroidism
• Hypoglycemia
• Anemia and nutritional deficiencies
• Sleep disturbances
• Cause unknown

DIAGNOSIS
A great number of factors must be considered when evaluating a patient with chronic fatigue. A detailed medical history and review of body systems goes a long way to identifying important factors. The goal is to identify as many factors as possible which may be contributing to the patient’s feeling of fatigue. For example, if a patient has heart disease, diabetes, or some other health condition, and the condition or the drug they are taking is clearly responsible for their fatigue, the treatment of their fatigue becomes secondary to the treatment of their underlying health condition.
In many cases of chronic fatigue, further evaluation is needed. The next steps can include a complete physical examination and laboratory studies. In the physical examination, look for any possible clues which may indicate the cause for the chronic fatigue. For example, swollen lymph nodes may indicate a chronic infection; and the presence of a diagonal crease on both ear lobes usually indicates impaired blood flow to the brain, a significant cause of fatigue in the elderly.
Avoid ordering expensive laboratory tests unless they are absolutely necessary. A complete blood count (CBC) and a chemistry panel (including serum ferritin in menstruating women) are useful as screening tools for other diseases. Avoid ordering laboratory tests to confirm a diagnosis that is not going to affect treatment. For example, if it is quite obvious that the patient has
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impaired immunity, it does not make much sense to perform elaborate and expensive blood tests on immune function because the results of these tests are not likely to influence the method of treatment.
Of particular value are assessment of liver detoxification function, bowel dysbiosis and gastrointestinal permeability (see Chs 9 , 16 and 21 ).
THERAPEUTIC CONSIDERATIONS
Since chronic fatigue and the CFS are generally multifactorial conditions, the therapeutic approach typically involves multiple therapies which address different facets of the clinical picture.
A person’s energy level, as well as their emotional state, is determined by an interplay between two primary factors – internal focus and physiology. Many people with chronic fatigue focus on how tired they are. They repeatedly reaffirm their fatigue to themselves and to anyone who will listen. Their physiology includes not only the chemicals and hormones floating around in the body, but also the way they hold their body (usually slouched) and the way they breathe (shallow). In most patients with chronic fatigue, both the mind and the body need to be addressed. The most effective treatment is a comprehensive program that is designed to help the use of their mind, attitude, and physiology to fuel higher energy levels.
Underlying health problems
Depression
The first factor to address is any underlying depression. Depression is one of the major causes of chronic fatigue and it is one of the common features of CFS. In the absence of a pre-existing physical condition, depression is generally regarded as the most common cause of chronic fatigue. However, it is often difficult to determine whether the depression preceded the fatigue or vice versa. Depression is fully discussed in Chapter 126 .
Stress
Stress is another factor to consider in the patient with chronic fatigue or CFS. Stress can be the underlying factor in the patient with depression, low immune function, or other cause of chronic fatigue (see Ch. 60 for guidelines for assessing the role of stress in chronic fatigue and CFS).
One of the tools we recommend to rate stress levels is the “Social Readjustment Rating Scale” developed by Holmes & Rahe.[13] The scale was originally designed to predict the likelihood of a person getting a serious disease due to stress. Various life-change events are numerically rated according to their potential for causing disease. Even events commonly viewed as positive, such as an outstanding personal achievement, carry with them stress.
Impaired liver function and/or environmental illness
Exposure to food additives, solvents (cleaning materials, formaldehyde, toluene, benzene, etc.), pesticides, herbicides, heavy metals (lead, mercury, cadmium, arsenic, nickel, and aluminum), and other toxins can greatly stress liver and detoxification processes. This exposure can lead to a condition labeled by many naturopathic and nutrition-oriented physicians as the “congested liver” or “sluggish liver” or the more recently coined “impaired hepatic detoxification”. These terms signify a reduced ability of the liver to detoxify. The congested or sluggish liver is characterized by a diminished bile flow, a condition known in medical terms as cholestasis, while impaired hepatic detoxification refers to decreased phase I and/or phase II enzyme activity. Phase I detoxification rates in excess of phase II activity will also cause toxicity problems due to excessive accumulation of activated intermediates (see Ch. 16 ). In addition to exposure to toxic chemicals, impairment of bile flow within the liver can be caused by a variety of other agents and conditions, as listed in Table 49.7 .
Although many of the conditions listed in the table are typically associated with alterations in laboratory tests of liver function (serum bilirubin, AST, ALT, LDH, GGTP, etc.), relying on these tests alone to evaluate liver function may not be adequate, as these tests are elevated only when the liver has been significantly damaged and many of these conditions in the initial or “subclinical” stages may have normal laboratory values.
TABLE 49-7 — Causes of cholestasis
• Dietary factors
—saturated fat
—refined sugar
—low fiber intake
• Obesity
• Diabetes
• Presence of gallstones
• Alcohol
• Endotoxins and other gut-derived bacterial toxins
• Hereditary disorders such as Gilbert’s syndrome
• Pregnancy
• Natural and synthetic steroid hormones
—anabolic steroids
—estrogens
—oral contraceptives
• Certain chemicals or drugs
—cleaning solvents
—pesticides
—antibiotics
—diuretics
—non-steroidal anti-inflammatory drugs
—thyroid hormone
—viral hepatitis

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Although there are more sensitive tests to determine the functional activity of the liver, such as the serum bile acid assay and various clearance tests (see Ch. 16 ), clinical judgment based on medical history remains the major diagnostic tool for the “sluggish liver” or impaired hepatic detoxification enzymes, the presence of chronic fatigue being the hallmark symptom.
People with a sluggish liver may also complain of, among other things:
• depression
• general malaise
• headaches
• digestive disturbances
• allergies and chemical sensitivities
• premenstrual syndrome
• constipation.
Not surprisingly, these are the same types of symptoms that people exposed to toxic chemicals often complain of. Many toxic chemicals (especially solvents) and heavy metals (see Ch. 18 ) have an affinity to nervous tissue, giving rise to a variety of psychological and neurological symptoms, such as:[14] [15]
• depression
• headaches
• mental confusion
• mental illness
• tingling in extremities
• abnormal nerve reflexes
• other signs of impaired nervous system function.
A hair mineral analysis is a good screening test for heavy metal toxicity. If the hair mineral analysis is inconclusive, a more sensitive indicator is the 8 hour lead mobilization test. This test employs the chelating agent EDTA (edetate calcium disodium) and measures the level of lead excreted in the urine for a period of 8 hours after the injection of EDTA.
An interesting multiclinic research study of chronically ill patients, many of whom were diagnosed as suffering from CFIDS, evaluated the efficacy of a comprehensive detoxification program. Patients were placed on a hypoallergenic diet and provided a dietary food supplement rich in nutrients that facilitate liver detoxification. The patients reported a 52% reduction in symptoms after 10 weeks and symptom improvement was mirrored by normalization of hepatic phase I and phase II detoxification.[16]
Excessive gastrointestinal permeability
Excessive gastrointestinal permeability, as measured by the lactulose/mannitol absorption test (see Ch. 21 ), is a common finding in CFS.[17] A treatment program utilizing food allergy control, nutrients to stimulate gastrointestinal regeneration and to support hepatic phase I and II detoxification, and an oligoantigenic rice protein food replacement formula was provided to 22 patients who fulfilled the classic CDC/NIH criteria for CFS. The patients’ average duration of CFS was 4.6 years. The treatment resulted in symptom reduction in 81.2% of the patients, with clinical improvement being paralleled by normalization of gastrointestinal permeability and hepatic detoxification function.[18]
Impaired immune function and/or chronic infection
When the immune system is impaired, infections can linger and fatigue persist. There is a good reason for fatigue during an infection – fatigue is the body’s response mechanism to infection because the immune system works best when the body is at rest.
In order to determine the role that the immune system is playing in patients with chronic fatigue, the series of questions listed in Table 49.8 can be utilized during the patient interview to indicate an impaired immune system. Chapter 20 describes in substantial detail the laboratory methodologies for assessing immune function.
Chronic Candida infection
One of the most common findings in individuals with impaired immune function is gastrointestinal overgrowth of Candida albicans. Candidal overgrowth is now becoming recognized as a complex medical syndrome also known as “the yeast syndrome” and “chronic candidiasis”. This overgrowth is believed to cause a wide variety of symptoms in virtually every system of the body, with the gastrointestinal, genitourinary, endocrine, nervous, and immune systems being the most susceptible. Table 49.9 lists the typical chronic candidiasis patient profile (see Ch. 48 for a comprehensive discussion).
The diagnosis of chronic candidiasis is often quite difficult as there is no single specific diagnostic test. Stool cultures and elevated antibody levels to Candida are useful diagnostic aids, but they should not be relied upon for diagnosis. The best method for diagnosing chronic candidiasis in most cases is a detailed medical history and patient questionnaire (see Appendix 2 ). Table 49.10 lists the factors that typically predispose a patient to candidal overgrowth.
TABLE 49-8 — Questionnaire for recognition of impaired immune function
• Do you get more than two colds per year?
• When you catch a cold, does it take more than 5–7 days to get rid of the symptoms?
• Have you ever had infectious mononucleosis?
• Do you have herpes?
• Do you suffer from chronic infections of any kind?

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TABLE 49-9 — Typical chronic candidiasis patient profile
• Sex: female
• Age: 15–50 years
General symptoms
• Chronic fatigue
• Loss of energy
• General malaise
• Decreased libido
Gastrointestinal symptoms
• Thrush
• Bloating, gas
• Intestinal cramps
• Rectal itching
• Altered bowel function
Genitourinary system complaints
• Vaginal yeast infection
• Frequent bladder infections
Endocrine system complaints
• Primarily menstrual complaints
Nervous system complaints
• Depression
• Irritability
• Inability to concentrate
Immune system complaints
• Allergies
• Chemical sensitivities
• Low immune function
Past history
• Chronic vaginal yeast infections
• Chronic antibiotic use for infections or acne
• Oral birth control usage
• Oral steroid hormone usage
Associated conditions
• Premenstrual syndrome
• Sensitivity to foods, chemicals, and other allergens
• Endocrine disturbances
• Psoriasis
• Irritable bowel syndrome
Other
• Craving for foods rich in carbohydrates or yeast

TABLE 49-10 — Factors predisposing to Candida overgrowth
• Impaired immune function
• Anti-ulcer drugs
• Broad-spectrum antibiotics
• Cellular immunodeficiency
• Corticosteroids
• Diabetes mellitus
• Excessive sugar in the diet
• Intravascular catheters
• Intravenous drug use
• Lack of digestive secretions
• Oral contraceptive agents

Food allergies
As far back as 1930, chronic fatigue was recognized as a key feature of food allergies.[19] Originally, Rowe & Rowe [19] used the term “allergic toxemia” to describe a syndrome that included the symptoms of fatigue, muscle and joint aches, drowsiness, difficulty in concentration, nervousness, and depression. Around the 1950s, this syndrome began to be referred to as the “allergic tension-fatigue syndrome”.[20] With the popularity of CFS, many physicians and others are forgetting that food allergies can lead to chronic fatigue. Furthermore, between 55 and 85% of individuals with CFS have allergies. For more information on food allergies, see Chapter 15 .
Hypothyroidism
Hypothyroidism is a common cause of chronic fatigue. However, the condition is often overlooked. The reason for this may be the reliance on standard blood measurements of thyroid hormone levels as the method of diagnosis.[21] [22] [23] Undiagnosed hypothyroidism is a serious concern as failure to treat such a critical and underlying problem will reduce the effectiveness of every other measure designed to increase energy levels. For more information, see Chapter 162 .
Hypoglycemia
The association between hypoglycemia and fatigue is well known. What is not as well known is the role that hypoglycemia plays in contributing to depression. Numerous studies have shown that depressed individuals suffer from hypoglycemia.[24] [25] [26] [27] Since depression is the most common cause of chronic fatigue, hypoglycemia must always be ruled out (see Ch. 161 ).
Hypoadrenalism
Adrenal exhaustion was first proposed as a cause of chronic fatigue over 50 years ago by Tintera.[28] A small, but growing, body of evidence now supports the role of a disruption of the hypothalamic–pituitary–adrenal axis (HPA) in CFS.[29]
One of the major symptoms of glucocorticoid deficiency is debilitating fatigue. Glucocorticoid insufficiency is also characterized by a stressing event followed by feverishness, arthralgias, myalgias, adenopathy, post-exertional fatigue, exacerbation of allergic responses and disturbances of mood and sleep, i.e. the typical presentation of CFS. These symptoms are seen in partial or subclinical adrenal insufficiency, which may only be detected by the ACTH stimulation test or other endocrine testing. Glucocorticoids have a very profound endogenous immunosuppressive effect. In subclinical adrenal insufficiency, this may allow for the symptoms of chronic fatigue, including exacerbation of allergic responses, enhanced antibody titers to a variety of viral antigens, and elevations in cytokine levels. A group of CFS researchers believe that these patients form a heterogenous group with a variety of infectious and non-infectious antecedents.[29] They feel that chronic fatigue syndrome
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does not represent a discrete disease with a singular cause, but rather a clinical condition. Chronic fatigue syndrome is analogous to a number of complex medical conditions such as hypertension in which a variety of direct and indirect factors lead to the development of the clinical syndrome.
The researchers hypothesize that in chronic fatigue syndrome, specific pathophysiological antecedents, such as acute infection, stress, and pre-existing or concurrent psychiatric illness, may ultimately converge in a final common biological pathway resulting in the clinical syndrome of chronic fatigue syndrome. They believe that their data and others suggest that a reduction in adrenal cortical secretion is an important pathophysiological component in the development of many of the biological and behavioral features of the syndrome.
For example, in one of their studies, 30 patients with classically defined chronic fatigue syndrome were compared with 72 normal volunteers and patients.[30] The CFS patients were found to have significantly reduced evening cortisol levels and low 24 hour urinary free cortisol excretion. The CFS patients also had elevated basal ACTH concentrations and increased adrenal cortical sensitivity to ACTH, but a reduced maximal response, and showed attenuated net integrated ACTH response to corticotrophin-releasing hormone. These results are most compatible with a mild, central, adrenal insufficiency, secondary to either a deficiency of CRH or some other central stimulus to the pituitary–adrenal axis. The authors feel that the hyperresponsiveness of the adrenal cortex to ACTH in patients with chronic fatigue syndrome may reflect a secondary adrenal insufficiency in which adrenal ACTH receptors have become hypersensitive due to inadequate exposure to ACTH. The reduction in response to large doses of ACTH might suggest overall adrenal atrophy. The evidence suggests that the mild hypocortisolism in these patients reflects a defect at or above the level of the hypothalamus, resulting in deficiency in the release of CRH and/or other secretagogs that serve to activate the pituitary–adrenal axis.
Mind and attitude
The mind and attitude play a critical role in determining the status of the immune system and energy levels. Many patients with chronic fatigue (including CFS) are either depressed or just seem to have lost a sense of real enthusiasm for life. Of course, it is not easy to have a lot of enthusiasm when you do not have much energy. But the two usually go hand in hand.
The first step is to convey to CFS patients that they can get better. Many patients with CFS are told it is “something they will have to live with” and “there is no cure”. Achieving or maintaining a positive mental attitude is critical to good health and high energy levels, especially in patients with CFS. In order to achieve a positive mind, a person needs to exercise or condition the attitude, similar to the way in which one would condition the body. In order to help patients, prescribe mental exercises such as visualizations, goal setting, affirmations, and empowering questions as detailed in Chapter 126 .
Diet
Energy level appears to be directly related to the quality of the foods routinely ingested. Have patients adhere to the dietary guidelines given in Chapter 44 . It is especially important to eliminate or restrict caffeine and refined sugar.
Although acute caffeine consumption provides stimulation, regular caffeine intake may actually lead to chronic fatigue. While mice fed one dose of caffeine demonstrated significant increases in their swimming capacity, when the dose of caffeine was given for 6 weeks, a significant decrease in swimming capacity was observed.[31]
It is also interesting to note that several studies have found caffeine intake to be extremely high in individuals with psychiatric disorders. Another interesting finding is that the degree of fatigue experienced is often related to the quantity of caffeine ingested. In one survey of hospitalized psychiatric patients, 61% of those ingesting at least 750 mg/day (at least five cups of coffee) complained of fatigue, compared with 54% of those ingesting 250–749 mg/day, and only 24% of those ingesting less than 250 mg/day.[32]
Be aware that in patients who routinely drink coffee, abrupt cessation of coffee drinking will probably result in symptoms of caffeine withdrawal, including fatigue, headache, and an intense desire for coffee.[33] [34] Fortunately, this withdrawal period does not last more than a few days.
Nutritional supplements
Nutritional supplementation is essential in the treatment of chronic fatigue. A deficiency of virtually any nutrient can produce the symptoms of fatigue as well as render the body more susceptible to infection. Individuals with chronic fatigue require, at the bare minimum, a high potency multiple vitamin–mineral formula, along with extra vitamin C (3,000 mg/day in divided doses) and magnesium (500–1,200 mg/day in divided doses).
Magnesium
An underlying magnesium deficiency, even if subclinical, can result in chronic fatigue and symptoms similar to CFS. In addition, low red blood cell magnesium levels, a more accurate measure of magnesium status than
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routine blood analysis, have been found in many patients with chronic fatigue and CFS. Several studies have shown good results with magnesium supplementation.
For example, in one double-blind, placebo-controlled trial, 32 CFS patients received an intramuscular injection of either magnesium sulfate (1 g in 2 ml injectable water) or a placebo (2 ml injectable water) for 6 weeks. At the end of the study, 12 of the 15 patients receiving magnesium reported, based on strict criteria, significantly improved energy levels, better emotional state, and less pain. In contrast, only three of the 17 placebo patients reported that they felt better and only one reported improved energy levels.[35]
This study seems to confirm some impressive results obtained in clinical trials during the 1960s on patients suffering from chronic fatigue.[36] [37] [38] [39] These studies utilized oral magnesium and potassium aspartate (1 g each) rather than injectable magnesium. Between 75 and 91% of the nearly 3,000 patients studied experienced relief of fatigue during treatment with the magnesium and potassium aspartate. In contrast, the number of patients responding to a placebo was between 9 and 26%. The beneficial effect was usually noted after only 4–5 days, but sometimes 10 days were required. Patients usually continued treatment for 4–6 weeks; afterwards fatigue frequently did not return.
Injectable magnesium is not necessary to restore magnesium status.[40] Absorption studies indicate that magnesium is easily absorbed orally when it is bound to aspartate or citrate. In addition, both of these compounds may also help fight off fatigue. Aspartate feeds into the Krebs cycle, the final common pathway for the conversion of glucose, fatty acids, and amino acids to chemical energy (ATP), while citrate is itself a component of the Krebs cycle. Krebs cycle components including aspartate, citrate, fumarate, malate, and succinate usually provide a better mineral chelate, as evidence suggests that minerals chelated to the Krebs cycle intermediates are better absorbed, utilized, and tolerated compared with inorganic or relatively insoluble mineral salts, including magnesium chloride, oxide, or carbonate.[40] [41]
Other therapies
Breathing, posture, and bodywork
Proper care of the body is critical to high energy levels. Breathing with the diaphragm, good posture, and bodywork (massage, spinal manipulation, etc.) are all important in helping to relieve the stress that is a common contributor to fatigue.
Exercise
Exercise alone has been demonstrated to have a tremendous impact on improving mood and the ability to handle stressful life situations.[42] Regular exercise has also been shown to lead to improved immune status. For CFS patients, regular exercise has been shown to lead to a significant increase (up to 100%) in natural killer cell activity.[43] [44] Although more strenuous exercise is required to benefit the cardiovascular system, light to moderate exercise may be best for the immune system. One study found that immune function was significantly increased by the practice of t’ai chi exercises.[45] T’ai chi is a martial art technique which features the movement from one posture to the next in a flowing motion that resembles dance. The research thus far suggests that light to moderate exercise stimulates the immune system, while intense exercise (e.g. training for the Olympics) can have the opposite effect.[46]
Botanical medicine
Eleutherococcus senticosus
In addition to supporting adrenal function and acting as a non-specific adaptogen, Siberian ginseng has been shown to exert a number of beneficial effects on immune function that may be useful in the treatment of CFS. In one double-blind study, 36 healthy subjects received either 10 ml of a fluid extract of Eleutherococcus senticosus or placebo daily for 4 weeks.[47] The group receiving the Siberian ginseng demonstrated significant improvements in a variety of immune system parameters. Most notable were a significant increase in T-helper cells and an increase in natural killer cell activity – both of which are of value in the treatment of CFS.
Glycyrrhiza glabra
Considering the possible roles of viral infection and hypoadrenalism in CFS, licorice root with its antiviral and glucocorticoid potentiating properties (see Ch. 90 for documentation of these properties) would seem to be an ideal botanical for this condition.[48] Unfortunately, this has not been rigorously evaluated, although an excellent response in a single patient has been reported.[49] The whole root must be used as DGL has had the glucocorticoid potentiating glycyrrhizic and glycyrrhetinic acids removed.
THERAPEUTIC APPROACH
Successful treatment of CFS requires a comprehensive diagnostic and therapeutic approach. Especially important is identifying underlying factors which may be impacting energy levels or the immune system. The strong correlation between chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivities suggests that all may respond to hepatic detoxification, food allergy control, and a gut restoration diet.[16] [17] [18] [50] Special
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attention should be paid to the advice on immune support in Chapter 53 .
Diet
Identify and control food allergies. Increase the consumption of water while eliminating consumption of caffeine-containing drinks and alcohol. Strongly suggest a diet of whole, organically grown foods. Control hypoglycemia through the elimination of sugar and other refined foods and the regular consumption of small meals and snacks. To speed the detoxification process, consider prescribing a course lasting for several weeks of a medical food replacement such as one of the UltraClear products.
Lifestyle
Teach the patient diaphragmatic breathing and a proper posture. Prescribe a regular exercise program; low intensity activities may produce greatest benefits.
Supplementation
• High potency multiple vitamin and mineral formula according to guidelines given in Chapter 44
• Vitamin C: 500–1,000 mg three times/day
• Vitamin E: 200–400 IU/day
• Thymus extract: 750 mg of the crude polypeptide fraction once or twice daily
• Magnesium bound to citrate or Krebs cycle intermediates: 200–300 mg three times/day
• Pantothenic acid: 250 mg/day.
Botanical medicines
• Eleutherococcus senticosus
—dried root: 2–4 g
—tincture (1:5): 10–20 ml
—fluid extract (1:1): 2.0–4.0 ml
—solid (dry powdered) extract (20:1 or standardized to contain greater than 1% eleutheroside E): 100–200 mg
• Glycyrrhiza glabra
—powdered root: 1–2 g
—fluid extract (1:1): 2–4 ml
—solid (dry powdered) extract (4:1): 250–500 mg
Counseling
Either counsel the patient directly or refer him or her to a professional counselor to establish a regular pattern of mental, emotional, and spiritual affirmations.