Introduction:

At various stages of my medical career I have encountered patients who simply baffled me. As a sophomore student beginning Physical Diagnosis at Charity Hospital in New Orleans, I was stumped for the first of many times: An older woman saw me in my new white coat and asked me if she could axe me a question. Feeling thrilled by being called "doctor" and a little buzz of authority, I readily agreed. Then she asked how it was possible that she could have both "high blood" and "low blood" at the same time. As yet unfamiliar with routine CH-NO slang for hypertension and anemia, I stood with my mouth open and a rabbit-in-the-headlights look. It was an intensely uncomfortable feeling, though my interrogator was kind and understanding.

Never mind professors and senior house staff, who are considerably less gentle on rounds and various conferences. Forget those probing questions from patients armed with medical articles from the internet and their families. Beyond even lawyers and regulatory agencies and insurance companies, the thing that bothers me the most is a patient who leaves me perplexed. We physicians are generally a group of perfectionists, and the only thing tougher than trying to help a patient for whom medical science has nothing to offer is having in our exam chairs an obviously sick person about whom we have no clue. That's why we have specialists.

Patients with Chronic Fatigue Syndrome (CFS) baffle even specialists. Actually, they are baffling all of the specialists. We shall review briefly the history of this affliction. It seems that patients have been struggling through physicians' offices with albatrosses around their necks for a very long time indeed. Earnestly hoping to help these patients and bearing in mind that one generation's crocks are the honored patients of the next (General Patton slapped a PTSD patient during WWII), intense efforts have been made to identify, define and then study CFS patients using the best of our currently accepted medical knowledge. All of these efforts, producing reams of publications from many nations, have failed to give us a definite answer.

At some point, it comes clearly to the student that these many researchers with different backgrounds, training and fundamental understandings are like the storied blind men with the elephant. Can it be that each has fastened onto a different part of a much larger whole? Can the clinician combine information about the many aspects of this conundrum to heal their patients? Published results are not terribly encouraging.

Having worked with chronically fatigued patients with increasing frequency for more than ten years, I have come to believe that the blind men describing their respective "parts" are not describing a single elephant, nor even several exotic zoo animals. It seems that our researchers and clinicians may be reporting on a variety of ordinary beasts well known to us, simply out of context. Like turning a corner in downtown Washington, D.C. and running into a large horse bearing a mounted policeman, the physician feels a little startled at meeting even something ordinary in an unexpected circumstance. In the case of CFS, the patients seem to be out of context, but why? It is because standard laboratory results do not substantiate their complaints.

Diligent efforts by regiments of researchers have resulted in the documentation of a variety of laboratory, radiological or other abnormalities. These tests run to the exotic and relatively obscure, as the following review demonstrates. The last portion of this text will examine instead the question: Could common disorders like thyroid disease, adrenal dysfunction and insulin resistance underlie CFS? While staying within the precincts of currently accepted medical fact, it is possible to show that a different point of view may completely alter what is seen. Any Otolaryngic allergist who has been told by an internist that "allergy" can be only IgE-mediated, that the only symptom of allergy can be hay-fever, will understand this approach.


Historical Background:

Fatigue is commonly a symptom of illness. As we look back upon the scientific limitations of our professional predecessors, it is not surprising that many patients with symptoms of fatigue went without a diagnosis. Beginning our review in the 19th century, in the days when Pasteur and Lister were developing their theories on sepsis, DaCosta described severe exhaustion following acute gastroenteritis among veterans of the American Civil War (1).

The American neurologist, George Beard, M.D. introduced the term "neurasthenia" (2) which has been noted to parallel CFS (3,4). It is observed that Beard believed that the patient's bodily energy was depleted by stress, which dissipated force from critical homeostatic centers (5). In the light of modern times, his assertions that steam power and the telegraph contributed to this exhaustion seem silly, even earning him the amused disbelief reserved for Clinical Ecologists. Remember, however, that stress has a direct effect upon the adrenals (6). We shall later review the potential role of adrenal dysfunction in CFS.

A number of occurrences of mysterious illness characterized by fatigue have been reported at intervals and scattered locations, described variously as "simulating poliomyelitis" (7, 8), Encephalomyelitis (9) and Neuromyasthenia (10). The term "Myalgic Encephalitis" has been widely used by the British (11). Each of these reveals the authors' impression that the ailment is somehow post-infectious. It is therefore understandable that the 1985 "outbreak" described around Incline Village at Lake Tahoe would also be attributed to a viral origin (12, 13). In this latter episode, an extremely plausible hypothesis had been offered, identifying the Epstein-Barr virus, which possesses extraordinary adaptations that enable it to enter and dwell within the human body indefinitely (14). The patients were genuinely ill, the virus was worthy of study and the game was afoot.

The national media decided this was newsworthy. The malady was given the nonchalant sobriquet "Yuppie Flu". Although the AIDS epidemic soon swept CFS from the headlines, chronically fatigued patients were so numerous and perplexing that the Centers for Disease Control increased their involvement. A working group was convened to establish a definition for this syndrome, which they recommended naming "Chronic Fatigue Syndrome". Their criteria for inclusion were published in 1988 (15) and then revised in 1994 (16), see tables one and two. The revised criteria show that investigators had turned away from their earlier emphasis on post-infectious causes of CFS and had discarded any reliance upon physical signs. The new, more specific list of medical diagnoses for exclusion must also reflect clinical lessons.

The validity of the CDC criteria has been examined and validated for research purposes by several studies (17, 18, 19). These show that patients meeting these guidelines are a clinically separate set, apart from patients with good health, Multiple Sclerosis, depression (17) and other chronic illness. There is, however, considerable agreement that this set of patients is heterogeneous (20), one strong study having evaluated 565 patients (21). This challenges efforts to create a distinct, separate and homogeneous group for study, as suggested by Buchwald (22).

Patients earnestly seek a diagnosis for their symptoms. I've seen patients weep in frustration as they tell of their journeys from physician to physician. One woman who had been repeatedly told she needed to see a psychiatrist spoke of her chagrin when upon finally being evaluated by one, she was told that she had no psychiatric problem. Through her tears she said: "I'm willing to be crazy if that will explain why I feel so bad!" Though many physicians seem reluctant to make the diagnosis of CFS and debate has occurred, it is beneficial to validate the patient with a single coherent and appropriate diagnosis (23, 24). In my opinion, it is then essential to seek further the causes for the patient's CFS.

Various reports are made which validate questionnaires in CFS. These instruments may aid in both diagnosing and monitoring progress of patients (25,26).

Schooley notes an important caveat. He notes that the case definition is less useful in making a diagnosis in individual patients than in giving a "general frame of reference". He states the CDC definition ",,, should not be used as a rigid checklist with which to rule the syndrome in or out in an individual patient. The diagnosis remains one of exclusion,,,"(27).

The CDC criteria are designed to enable proper epidemiological and medical study of groups of CFS patients. And what a lot of work has been done! Using these as well as British criteria (28) and Australian, often in combination, there are as of September 1, 2000 no less than 1,951 titles published in "respectable" medical journals available on the National Library of Medicine's excellent "Pub Med". It is certainly much easier to find interesting research on CFS than it is to understand it.


Epidemiology of Chronic Fatigue Syndrome

From the 19th century, it was thought that fatigue syndromes were an affliction or an affectation of women of the wealthy class (5). We now perceive that these may have been simply those who could afford to seek care. Modern studies have shown that while a preponderance of women suffer from CFS compared to men by a relative risk of 1.3 to 1.7 (29), this is not an illness of the affluent. Well executed telephone surveys in Chicago (30) and San Francisco (31) agree that highest levels are found among women, some minorities and persons of less education and lower income.

The prevalence of CFS has repeatedly been studied. Across broad population groups, the point prevalence in the U.S. may be 0.075 to 0.267% (32), 0.2% (31), or 0.42% (30). Rates in England were similar at 0.5% (33) but much lower in Japan at just 0.85 per 100,000 (34). This may correlate with an observation that in the U.S., the lowest prevalence was among Asians (31).

Certainly, patients who meet the CDC criteria for CFS are far outnumbered by patients who are simply chronically fatigued. Indeed, the complaint of chronic fatigue is one of the most common in many illness and may occur in as many as 20% of patients attending a general medical clinic (35). The ratio of patients with "true" CFS to those with idiopathic chronic fatigue (ICF) (16) varies among reports, from a high of 1:3 (36) to 1:8 (33) and 1:9 (31) to a low of 1 to 24 (32). It is noteworthy that the study reporting the lowest U.S. incidence of CFS also records the lowest ratio of CFS to ICF patients (32), suggesting that application of the CDC criteria in an accurate and uniform manner may be difficult. This difficulty has even been recently stated by Fukuda, himself (37).

Before undertaking more specialized evidence, we will note that some epidemiological studies have refuted the suggestion that CFS could be a post-viral syndrome (38, 39), though another reports an increased rate of onset of illness with certain seasons (November – January and again in April – May) which the authors interpret as supporting an infectious etiology (40). There are, however, statistically significant associations between the onset of CFS and antecedent stress, either physical or psychological (38, 41). This may have significant bearing on later discussion of the roles, both adaptive and maladaptive, of the adrenal and thyroid glands.

Differential Diagnosis

Because the symptom of fatigue is so common among patients suffering from medical problems, the differential diagnosis of CFS is, in essence, vast. As suggested above, the true explanation for CFS may even be the inability of laboratory testing to demonstrate the diagnosis, for reasons which shall be discussed. Certainly, familiarity with the dilemma of sensitivity vs. specificity shows us that the more we rely of laboratory tests for specific diagnoses the more often we may fail by diminished sensitivity. I recall Dr. Fred Stuckey, my professor of Medicine at Tulane fussing that no test can "rule out" any diagnosis, only "rule in". He may well have been correct.

Fibromyalgia Syndrome

The first undertaking shall be a consideration of Fibromyalgia (FM). Goldenberg has described this syndrome in a clear and thorough review (41). He shows that between 10% and 12% of the general population has chronic widespread pain. The need to study these patients has led to the formulation of diagnostic criteria for FM.

The American College of Rheumatology classification of 1990 (42) was based upon a blinded study comparing 293 FM patients with persistent generalized idiopathic pain to 265 "control" patients with regional chronic musculoskeletal pain or a systemic rheumatic disease. The symptom of chronic widespread pain and the finding of mild or greater tenderness to finger pressure in at least 11 or 18 specified locations gave a sensitivity of 88% and specificity of 81% in distinguishing between FM and the other causes of chronic pain. The study committee interestingly found no difference in patients with FM who had a concurrent medical condition. Therefore, the criteria make no distinction as to co-morbid illness.

Goldenberg then illustrates this significant conceptual difference between FM and CFS: FM is accepted as co-existing with many illnesses, rather that being a ?diagnosis of exclusion?. It is, for example, found in 10% to 40% of systemic lupus erythematosus and 10% - 30% of rheumatoid arthritis patients.

Other investigators have examined the epidemiology of FM. Buchwald recorded a significant gender difference in diagnosis of FM among 348 CFS patients. Women with CFS had significantly more FM than men, 36% vs. 12% (43). This gender bias was not apparent in a smaller Canadian study (44).

Reports have studied the co-incidence of CFS and FM. One group of 402 chronically fatigued clinic patients could be subdivided into CFS (37%), FM (7%), and both in 15%. The remainder were considered ICF (45). Recently, 74 patients with FM were found to meet 1988 CDC criteria for CFS in 58% of the women and 80% of the men. These percentages were considerably higher than those of two control groups (44).

Goldenberg addresses the debate over the exact relationship between FM and CFS. Citing various reports, he states his belief that FM, CFS and irritable bowel syndrome overlap so extensively that they ought to be considered different presentations of the same general condition. This statement is supported elsewhere in at least three other review articles (46, 47, 48). A multi-center study compared the frequency of ten clinical conditions among patients with CFS, FM, and temporomandibular disorder (TMD). They found that the three syndromes share many key symptoms, especially irritable bowel syndrome (IBS)(49). This was reaffirmed by a British study of 1,797 chronically fatigued patients, of whom 63% fulfilled criteria for IBS (50).

Klein and Berg report a study of autoantibodies which shows close correlation between FM and CFS (51). Antibodies to 5-HT (serotonin) were closely related with FM/CFS. Antibodies to gangliosides and phospholipids were common, yet could also be detected in other disorders.

With this agreement, it is noteworthy that there are indeed objective laboratory findings that differentiate CFS from FM. Levels of substance P (a cytokine associated with pain) in the CSF of FM patients is generally elevated, but not in CFS patients? CSF (confused yet? Say it three times quickly.)(52). In addition, somatomedin C (a breakdown product of growth hormone with much longer plasma life, also called Insulin-like growth factor I, ILGF-1) are found to be higher in 49 CFS patients than in 30 healthy matched controls, while lower in FM patients (53). The authors state that different abnormalities of the somatotropic neuroendocrine axis and/or sleep must exist for CFS and FM.

Again Goldenberg provides a framework for resolution of these disparate facts. He states that patients with FM are found to have a generalized hypervigilance to both pain and auditory stimulus (otologists puzzled by hyperacusis take note!) with qualitatively altered nociception. This is now generally believed to be a manifestation of altered central nervous system processing of nociceptive stimuli, citing numerous publications (41). This can explain the diversity of causal associations with the onset of this syndrome. It also may explain the observed relationship between such seemingly disparate entities as FM and interstitial cystitis which are found to significantly overlap (54).

In summary, then, it seems that Fibromyalgia Syndrome is interwoven with CFS. There are some differences, which ought to surprise none, given the significant differences in pain perception between CFS patients with and without FM. Fukuda et al?s ?figure 1? in their 1994 publication is a good visual tool to understand these relationships (16).

Diagnostic Considerations:

CFS is a diagnosis of exclusion. No laboratory test can diagnose CFS or even gauge it?s severity. A careful history must be taken from the patient, with consideration of not just medical disorders but psychiatric status and, obvious as it seems, sleep history. Esoteric tests are ?reserved? for the use of esoteric university professors (35).

A list of some conditions that can explain chronic fatigue is offered by the NIAID-NIH (55). These are shown in table 3. The thyroid notification is particularly appropriate. Conspicuously absent are perimenopause and Addison?s disease.

There are many smaller works suggesting that a variety of often unsuspected problems can lead to chronic fatigue. These may be grouped into rough categories for this review. Immunological problems include familial dysfunction of natural killer cells (56), celiac disease (57), dermatomyositis (58), and ?seronegative? Sjogren?s syndrome (59). Evidently, laboratory testing is not always reliable in making these diagnoses.

Various toxic conditions are cited as well, including fungal spores, which may either stimulate the immune system, well familiar to the Otolaryngic allergist, or poison us through its mycotoxins (60). Also noted are environmental toxins including lead (61), for which our standard blood tests are arguably imperfect (62), and carbon monoxide (63). Other more exotic toxins include chronic ciguatera poisoning in Australia (64) and the eosinophilia myalgia syndrome from contaminated L-tryptophan (65).

Various disorders may be grouped into ?metabolic problems?, of varied cause. These include syndrome of inappropriate anti-diuretic hormone (SIADH)(66), phosphate diabetes from abnormal renal tubular re-absorption, causing changes in mitochondrial respiration (67). Also, primary chronic magnesium deficiency (MD) is reported, for which the authors state: ?Normal concentrations of magnesium in blood do not rule out the diagnosis of the nervous form of primary chronic MD?(68). Our usual blood tests don?t make the diagnosis, you see. Also, Downey speculates upon the possible role of abnormal porphyrin metabolism (69).

The list of possible differential diagnoses must run on indefinitely. Beyond the variety and obscurity of some of these, it is noteworthy that so many authors cite failure of standard laboratory tests to make the correct diagnosis.

Laboratory evaluation

The NIH has suggested an initial laboratory work-up for possible CFS patients (55). This is presented in Table Four. From the perspective of an infectious diseases specialist, Schooley has suggested also a PPD, ELISA for HIV, Serologic studies for EBV or CMV and hepatitis A, B or C as indicated by abnormal hepatic transaminases (27). Writing in ?Harrison?s?, Straus suggests simply: ?Routine laboratory tests? (35). Our review shall include many non-routine tests as we attempt to explain facets of CFS.


An etiologic approach to understanding CFS

Psychiatric and neurological studies

The description of what is now called CFS predated the birth of modern psychiatry. Though Beard refused to accept a psychogenic explanation for neurasthenia, the disorder gradually fell into the burgeoning realm of psychiatry as it entered the 20th century. It is entirely understandable that an affliction of no known origin besides stressful events, with associated hypersensitivity to pain and attendant symptoms of mental confusion and depression should come under the scrutiny of psychiatrists, especially as it still, 100 years later, has no associated physical signs and no abnormalities on routine laboratory testing. Wessely defines a functional somatic symptom as one that, after appropriate medical assessment cannot be explained in terms of a conventionally defined medical disease (70). By that inclusive definition, psychiatrists certainly ought to become involved with CFS patients.

Barsky and Borus have written a splendid review (71). They agree with Wessely?s opinion that the number of specific somatic syndromes is largely an artifact of medical specialization. Further, they present a very good review of the psychosocial factors that amplify symptoms. Prospective studies of herpes zoster, heart disease, post-viral fatigue and two studies of CFS patients are cited which prove that the patient?s beliefs about their disease at the outset strongly influence the reporting of symptoms at follow-up. They also cite evidence that anxiety and depression amplify and perpetuate somatic symptoms. Well referenced comments on the role of future expectations and the role of suggestions are worth study.

Barsky ably demonstrates that psychological factors effect a patient?s perceptions and eventual outcome of an illness. There is, however, no evidence that CFS is solely a psychiatric problem. He lost that claim to this reader when he early on stated that food allergy, hypoglycemia and ?candidiasis hypersensitivity? were included among functional somatic syndromes. The first is well understood by the Otolaryngic allergist, the latter two shall be discussed below.

Patients with chronic fatigue are at greater risk for current psychiatric disorder than people without chronic fatigue (72). Yet Brunello et al., an international group?s review states that in every study, between one third to one half of CFS cases do not fulfill criteria for a psychiatric disorder - unless, of course, one claims that CFS is itself a psychiatric disorder (73).

Depression.

Efforts have been made to validate sundry questionnaires for the study of CFS patients (74, 75, 76, 77). One pressing question involves the frequent co-existence of CFS and depression. Using questionnaires, three series report significant differences between CFS and depressed patients (78, 79, 80). Of these, one has large numbers of patients and seems reliable (79). Only one recent paper failed to show a difference between these two groups, and this was a small study (81). It seems safe to state that while CFS patients are often depressed, CFS is not caused by depression.

A variety of other psychiatric disorders have been examined in relation to CFS. Brunello?s group notes that neuroendocrine profiles in CFS are closer to those observed in anxiety disorders than depression. Interest in post-traumatic stress disorder is expressed (73). A possible link with seasonal affective disorder is entertained for a subgroup of patients (82) but is emphatically dismissed by a study from the NIH (83). Other mention is made of possible association between CFS and the negative aspects of perfectionism (84).

Central nervous system: Cognitive and neurological

CFS patients complain frequently and emphatically that they have impaired cognition, often called ?brain fog?. Nine reports of cognitive functioning testing from 1994 to 1999 have validated abnormalities in CFS patients compared to various carefully chosen control groups. These studies are of similar size, with CFS patients numbering between 20 and 36. These CFS patients had significant problems in performance of visuomotor search and logical memory (85), attentional capacity (86), auditory processing (87), learning and memory (88), psychomotor slowing, impaired attention, learning rate, and delayed recall (89), motor cognition and cognitive processing (90), information processing (91), memory, attention and information processing(92), information processing and attention (93). Standing virtually alone against this flood of positive results is one negative report in which no differences could be found (94).

Objective measures of CNS function have been further evaluated. Two studies are found which show significant gait abnormalities which are thought to strengthen the hypothesis of a direct involvement of the CNS in the onset of CFS (95, 96).

Reports of other forms of testing which has been positive for CNS dysfunction include impaired acquisition of the classically conditioned eyeblink response indicating an associative deficit (97). Vestibular testing has shown central-type abnormalities (98). Cortical motor potentials have shown slowed reaction times and reduced premovement-related potentials (99). To the contrary, a test of P3(00) auditory potentials showed no difference between CFS patients and controls (100).

Studies of sleep

A common complaint among CFS patients is lack of good quality, refreshing sleep, primarily difficulty in staying asleep (101). A Welsh study found that 80% of CFS patients fulfilled both DSM-III-R and ICD-10 criteria for sleep disorders (75). Polysomnography has been performed in a variety of well-controlled studies and has been abnormal. Findings in the CFS groups include sleep initiation and sleep maintenance disturbances and decrease in stage 4 sleep (102, 103) with significantly more time in bed, less efficient sleep and longer time awake after sleep onset (104). It seems important to note that only 20% of CFS patients reported sleep continuity complaints prior to the onset of CFS symptoms (103).

Aroused by these issues, researchers have studied sleep EEG in groups of CFS patients. Several have reported alpha wave intrusions into non-rapid eye movement sleep (alpha-delta sleep) and K-alpha sleep to be significantly more common among patients with CFS (105, 106). A negative study was reported and discussed the importance of the electrode placement array (107).

Retaining intellectual ties with the post-infectious theories of CFS, consider the review of the influences of host – defense activation on sleep from the Max Planck Institute (108). Human and animal studies are reviewed. Some disorders of excessive sleep, daytime fatigue and disturbed night sleep are thought to at least in part involve immuno-pathologic mechanisms.

A note of caution is sounded by the Aussies (108). Four patients who had been diagnosed with CFS were found to actually have narcolepsy. Two were cured of symptoms and two much improved with methylphenidate treatment.

Central Nervous System imaging studies.

In a fine 1994 review article, Bell cites the technique of single photon emission computed tomography (SPECT) scan, which demonstrates perfusion (110). Of several studies then available, that of Ichise was large and convincing, demonstrating abnormal perfusion in several areas of the brain and brain stem in 80% of 60 CFS patients who were compared to 14 healthy controls. More recently, I find three studies, all of which have confirmed significant perfusion abnormalities in various regions of the brain and brainstem (111, 112, 113). One of these groups has compared SPECT to magnetic resonance imaging (MRI) and found no significant association of MRI abnormalities in 16 CFS patients compared to 15 controls (114). Though one of three other recent MRI studies is able to show a positive correlation (115), it is clear that MRI does not consistently show abnormalities in CFS patients (116, 117).

Taking the question beyond perfusion to metabolism, brain positron emission tomography (PET) has been used to study brain glucose metabolism. Tirelli and co-workers report a statistically significant hypometabolism in both mediofrontal cortex and brainstem in CFS patients compared to both healthy and depressed controls (118). Though doubtless valuable, the PET scan was less sensitive compared to SPECT scan, indicating that it is possible to have perfusion abnormalities of the brain without corresponding measurable decrease in glucose uptake (119). These two modalities clearly offer the best imaging evidence for CNS abnormalities in CFS .patients.

Neurotransmitter abnormalities

Neurotransmitter abnormalities have been studied. Demitrack and colleagues compared 19 CFS patients with 17 healthy controls, testing both CSF and peripheral blood for metabolites of neurotransmitters (120). Though no significant differences were found in the CSF, plasma levels of 5-HIAA (from serotonin) were significantly higher and MHPG (from nor-epinephrine) were significantly lower in patients. The fascinating fact here is that these data are exactly opposite from findings in depressed people. With so much overlap between CFS and depression, this opened an important door.

Cleare et al. give evidence that depressed patients have ?HPA overdrive? with raised cortisol exerting an inhibitory effect on central 5-HT neurotransmitter function (121). Referring to Demitrack?s 1991 report, they suggest that CFS may be just opposite to depression, with reduced HPA function and increased 5-HT function. Then, using 30 mg d-fenfluramine orally, a 5-HT releasing agent, and measuring both plasma cortisol and plasma prolactin levels (as a measure of 5-HT function) in a well controlled trial, their data are quite consistent with their hypothesis. Increased prolactin response to another 5-HT agonist (buspirone) is also reported in a controlled study (122). Unfortunately, a study similar to Cleare et al. although using twice as large a dose of dl-fenfluramine (60mg) has failed to note any significant differences (123).

Several other investigations relevant to serotonin are interesting. CFS patients were found to have significantly higher levels of plasma free tryptophan (the serotonin percursor) at rest which did not change during or after exercise (124). These were similar to levels of plasma tryptophan after major surgery. The authors felt this supported Cleare?s study.

Finally, in a study previously cited, autoantibodies to serotonin (5-HT) were present and closely related to CFS and FM (51). Forty-two CFS patients were tested with ELISA. Sixty two percent of the CFS patients and 73% of the FM patients were positive. Other antibody reactions were less specific.

Pharmacotherapy based on a neuro-psychiatric paradigm

With so much action in the serotonin camp, it is no surprise that selective serotonin re-uptake inhibitors (SSRI) are a mainstay of medical treatment for the symptomatic relief of CFS patients. Unfortunately, there is considerable disappointment in the results. Reid and Wessely are quite up to date in their review article and their lack of enthusiasm for SSRI therapy seems valid (125). Several well designed trials using fluoxetine (Prozac) have been equivocal. The first large double-blind, randomized, placebo controlled study of a large number of patients was impressively negative(126).

Monoamine Oxidase inhibitors and tricyclic antidepressants have also been carefully studied. There may be some improvement, mostly to concurrent depressive rather than to CFS symptoms. Some improvement with the tricyclics may be due to their analgesic effects. Amitriptyline benefits appear independent of mood effect. Side effects of some drugs may be considerable (125). Overall, it seems wise to reserve antidepressants for treatment of co-existing depression in CFS patients. Furthermore, it is proper to follow your patient?s response to the treatment and discontinue ineffective medications.

Cognitive behavior therapy (CBT)

Whatever triggers CFS may not perpetuate it (73). The rationale for CBT is based upon the understanding of the importance of these perpetuating factors in maintaining the disorder. As previously cited, there are strong associations between expectations about an illness and the eventual outcome (71).

In two randomized, controlled trials each of 60 patients, CBT has been proven successful (127, 128). Combined with medical care, 73% of CBT patients achieved a satisfactory outcome compared to just 23% with medical care alone (127). CBT was more effective than relaxation therapy both in functional impairment and fatigue measures. The improvements were sustained over six months of follow-up (128). The possible lack of availability of a trained CBT therapist may limit the usefulness of this modality of treatment.

Summary

Ample evidence of neurological impairments seem sufficient to demonstrate that CFS patients are ill, rather than just ?mental?. Doubtless, expectations, overlay and fears add to the burden of illness that the patient must bear. Previous history of psychiatric disorders may be common in these patients and co-morbid depression occurs frequently. It is very helpful to enlist a therapist?s assistance for the long-term management of patients with CFS.


The post-infectious hypothesis

Viruses

Many CFS patients point to an infectious illness that immediately predated the onset of their symptoms. Concern that CFS might be a lingering after-effect of an infection is reflected in the original CDC criteria for defining CFS (15). Many reports have made connection between CFS and a variety of agents. A brief review may be useful.

Every college student in the 1960s knew that some people who got mononucleosis might stay sick for months. With the interest in CFS that followed the reports from Nevada in the 1980s, it was natural to suspect the Epstein-Barr virus (EBV). This human herpesvirus may be highly pathogenic yet ?benignly? infects and persists for life in more than 90% of the adult human population, being found in memory B cells (14). Was this amazing little passenger causing disease, merely reactivating in a compromised host like a ?fever blister?, or simply innocent?

The EBV has been studied extensively. Impairments of performance and mood are very similar between acutely infected and months-convalescent patients compared to healthy controls (129).
Several early reports suggested a significant role for EBV in chronic illness (130, 131). A variety of small, controlled studies showed conflicting results and then Buchwald and co-workers seem to have quenched the EBV (and many other viruses) debate (132). In a controlled report of 548 CFS patients who were tested for antibodies to 13 viruses in addition to medical and psychiatric evaluation, no differences in seropositivity or geometric mean titer of antibodies could be shown compared to controls or any subsets of patients including those with acute onset or documented fever.

Experience with therapeutically administered Interferon-alpha showed clinicians that its side effects were often the same as CFS symptoms (133, 134). Promptly, many viruses were considered as possible causative agents for CFS. These are nicely reviewed in an excellent paper by Evengard et al. which is well up to date (135). Despite Buchwald et al., which would seem to have applied the coup de grace to post viral fatigue syndrome (PVFS)(132), interest, research and publications have continued.

Human herpesvirus-7 is virtually ubiquitous and seems innocent. (136). Human herpesvirus- 6 has been reportedly activated more often in CFS patients (136, 137, 138). It was one of the viruses tested and found negative in Buchwald et al (132). Even so, it is tropic to a wide number of human cells and is known to produce clinical encephalitis and in immuno-suppressed people is associated with demyelinating diseases (135). Interest persists, yet results still conflict (139).

Enterovirus infections may cause symptoms similar to CFS. Reports seem to put the Scots (140, 141, 142) against the rest of the world (143, 144) with the English being politely equivocal (145). The Glasgow group has found lots of enterovirus traces using polymerase chain reaction (PCR) assay, including distinctly novel enterovirus sequences (141). The Dutch and Swedish groups also used PCR and found negative results. The Swedes tested feces, even CSF and muscle biopsies (144). Reading about PCR, I understand how the O. J. Simpson jury felt when they heard about the DNA evidence. Maybe it is the haggis.

Borna disease virus (BDV) was suggested in Japan as a possibly linked to CFS (146). It is a neurotropic single-strand RNA virus, naturally infecting horses and sheep. Farm boys beware. Subsequently there is a great discrepancy between reports, one showing PCR assays positive in 8 of 25 CFS patients (147) but another in 1999, using a new assay technique, found no positives among 75 CFS patients (148). One questions the utility of the PCR assay.

A scattering of reports mention other viruses. Included are parvovirus B19 (one of one and none of 7 patients were positive)(149, 150) and Coxsackie B virus, none different from controls in two large studies (151, 152). Finally, the post-polio syndrome is mentioned briefly in this context (153). This was from the Post-Polio Institute, reviewing literature to make comparisons between PVFS and the sequela of post polio fatigue.

Other infectious agents

Much has been heard, especially in the northeastern U.S., about Lyme disease. Though controlled studies have been performed, limitations are apparent. One study which stated that the ?post-Lyme syndrome?(PLS), characterized by persistent arthralgias, fatigue and neuro-cognitive impairment is probably induced by Lyme disease appears to have done no more than compare a group of PLS sufferers to a group of fully recovered post-Lyme disease patients (154). They basically report that the sicker ones were sicker.

A more stimulating publication documents a prospective double-blind test of 1,156 healthy males for Lyme Borrelia antibodies. Seropositive subjects who had never manifested clinical Lyme disease showed significantly more frequent chronic fatigue and malaise than those seronegative (155). The authors reasonably suggest consideration of an antibiotic for CFS patients with positive Borrelia serology. Counterbalancing this paper is a controlled study of 39 CFS patients from the northeastern U.S. which found no reactivity on a Bb immune complex test (156). They state that patients lacking antecedent signs of Lyme disease are not likely to have laboratory evidence of Borrelia infection.

Two puzzling papers come from California. Both report large cohorts of CFS patients. Both report a very great amount of atypical Mycoplasma in DNA purified from blood samples using a PCR assay. In the first, Vojdani and associates found genomes for M. fermentans and Mycoplasma genus significantly more in CFS patients than in healthy controls, P< 0.0001. (157). All samples were confirmed by Southern blot with a specific probe based on internal sequences of the expected amplification product. Also, individuals with high genome copy numbers (i.e. a lot of Mycoplasma gemones per unit of DNA) had higher IgG and IgM antibodies against Mycoplasma specific peptides. Nasrulla et al. reported 91 CFS patients who had a positive test for any Mycoplasma (158). Forensic PCR assay for five different Mycoplasma species showed that 30.8% had double infections (multiple species) and 22% had triple infections. That?s a lot of species of one ?bug?.

The thing that puzzles me is that these strongly positive studies have been mainly ignored. Perhaps this is because of the high ratio of techno-jargon to fact, or possibly the originating institutions are not widely recognized. Note that the PCR assay is involved in two other controversies, Scotland vs. Europe and Borna ?yes? vs. Borna ?no?. I understand that this technology is remarkably specific, yet here are wide differences. In addition, there is much mention of ?novel sequences?. It seems that the test is giving results which may be subject to much misinterpretation. This concept is the theme of this review.

Finally, several individual papers are included. A British report suggest the existence of a chronic fatigue state following an outbreak of Q fever in England using a controlled, questionnaire method (159). Swanink et al. found no correlation between Yersinia enterocolitica and CFS in a controlled study of 88 patients. An immunoblot technique was used to detect IgG and IgA antibodies to various Yerisnia outer membrane proteins (160).

Retrovirus

The AIDS epidemic introduced us to the retrovirus. Naturally, attention was given to the possibility that this class of virus could be associated with CFS. Early studies were conflicting (161, 162). Through an interesting sequence of six reports, Martin evolves from electron microscope sleuth (voyeur?) spying an atypical virus cytopathic for fibroblasts which he called a ?stealth? virus (presumably in honor of Lockheed technology)(163) to having identified this stealth virus as one related to simian cytomegalovirus and beyond. He has inoculated this virus into cats and produced acute neurological illness (164). He has shown that some of these may have arisen from the live polio viral vaccines (165). He has used an extraordinarily nebulous phrase: ?a patient with chronic fatigue syndrome?. His largest series has been three patients (166).

Recently, another group of electron microscope jockeys in New Zealand reported structures similar in shape, size and character with a Lentivirus in 10 of 17 CFS patients and none in controls (167). The Kiwis were unable to identify a lymphoid phenotype containing these structures and results of a reverse-transcriptase assay were equivocal in this blinded and case controlled study.

Epidemiological analysis

With many and conflicting reports of viral and other infectious passengers found in some form or other in CFS patients, epidemiological methods have been employed. A British review of Q fever patients seemed to support the post-viral assertion (159). Buchwald et al. compared demographic, clinical and laboratory features in 717 patients with chronic fatigue with and without a self-reported postinfectious onset, and in particular the subset with CFS (168). They concluded that a postinfectious onset was not significant and could not differentiate between CF and CFS patients.

A prospective study of 245 patients with ?glandular fever? or an upper respiratory infection stated that the empirically defined fatigue syndrome probably is a valid condition in six months following glandular fever (169). Peculiarly, they chose psychiatric patients as case controls. How does that make you feel?

A better executed, controlled study compared 83 post-viral meningitis patients to 76 post-viral patients (non-CNS and non-enteroviral) over a six to 24 month follow-up (170). Several observations of note include: First, a rather high prevalence of CFS overall, 12.6%, though no difference existed between the groups. Secondly, the onset of CFS is predicted by psychiatric morbidity and prolonged convalescence, not by severity of the viral illness itself. These assertions about psychiatric co-morbidity are supported by two other works (171, 172).

The definitive work on postinfectious fatigue comes from Wessely et al. in London. The verdict is that common infectious episodes in primary care are not guilty of causing CFS (173). Their prospective study followed 1,199 persons aged 18 – 45 who presented to their general practitioners with symptomatic infections for six months, controlled by 1,167 people who attended for other reasons. At six months, 9.9% of cases and 11.7% of controls reported chronic fatigue. No effect of infection was noted. The strongest predictors of ?postinfectious fatigue? were fatigue or psychological problems at the baseline evaluation, in agreement with others (170, 171, 172).

Treatment based upon post-infectious paradigm

Several strategies for antiviral therapy have been studied. As a resident, I had some experience using interferon alpha (IF-a) for pediatric viral laryngeal papillomatosis. Application of IF-a to CFS patients was reported by See and Tiles in 1996 (174). Thirty patients were treated with alpha 2a interferon or placebo in a double-blind crossover study. Many immunological parameters were measured and a 10 item quality of life questionnaire was used. There was no effect of treatment except upon a subset of seven patients whose only abnormality was isolated Natural Killer (NK) cell dysfunction. Their NK cell function increased as did their symptom questionnaire scores. Please note that improvement in this case does not mean ?well?.

Anti-viral drugs have been applied with varying results. Interferon and acyclovir were combined to successfully treat one patient with a dramatic presentation of well documented chronic active EB virus (175). This paper supported the hypothesis of endogenous reactivation of EB virus.

Strayer et al.?s 1994 multi-center randomized, placebo controlled successful treatment of 92 CFS patients with an antiviral and immunomodulatory drug, poly(I).poly(C12U)(Ampligen) yielded significantly (just barely) superior results across many measures, including treadmill work tolerance, reduced cognitive deficit and reduction of daily medicines (176). From another 1994 paper on the same clinical trial by some of the ?et al.? authors and their subsequent work (177, 178), it seems that the success of the drug was due to its immunomodulatory effect, not its antiviral action.

Amantadine has been used in two groups of patients. In one trial the results seemed promising but only four patients were studied, one of whom had already gotten a good result with prior treatment with amantadine (179). Other questions, like that of controls (?methinks the lady protests too much?), lessen the impact of this report. A larger series of 30 patients not only demonstrated no statistically significant improvement but the side effects of the drug were so intolerable that half of the study group dropped out (180).

Summary

The postinfectious hypothesis has not been supported. Many CFS patients report a febrile illness just before the onset of their fatigue. Many throat cancer patients in my residency clinic had identified some antecedent event which they believed had caused their throat symptoms. That much is ?human nature?. Illnesses with viral symptoms are common.

Though discounted as a cause of CFS, there exist lingering questions about antecedent or associated viral infections which may offer fertile soil for a future re-growth of interest. Could these infections which seem to herald the onset of CFS actually initiate if not perpetuate the problem? Beyond simply being the final stressful event that is ?the straw that broke the camel?s back?, might they alter host defenses? Could there be some deleterious immune response like post-streptococcal antistreptolysin-O, or the molecular mimicry of Reiter?s syndrome? It is hard to resist making these self-indulgent speculations, which have no basis other than analogy. Analogy, however, is a powerful tool (181).


Immunological abnormalities

Because CFS patients report so many symptoms that suggest an infectious etiology, it has been speculated that an overproduction of one or more cytokines that can be triggered by any infectious agent (27). Schooley adds an alternative hypothesis: Any of a number of infectious agents might establish a regulatory imbalance of cytokines which the host subsequently might be unable to restore to a proper balance. Cytokines may disrupt neurotransmitter function and result in the symptoms of CFS (135).

Studies of cytokines

Combining the reviews of Bell (110) and Evengard (135) with more recent publications, we find sixteen interesting controlled studies of cytokines in CFS patients (182 – 197). Displaying the results of these studies in a tabular format, one can see that there is little unanimity.

Neopteryn is the only cytokine which has given abnormal results in every study reviewed (182, 185, 186). This is a marker of macrophage activation. Its consistent elevation indicates immunological stimulation in CFS.

Tumor necrosis factor-alpha (TNF-a, cachectin) may cause symptoms of pain, inflammation fatigue and somnolence in vivo (197). Serum TNF-a is significantly abnormal in a large retrospective controlled study of 240 CFS patients compared to 240 controls. Thirty two percent of CFS patients and only 7% of controls had elevated levels above 50pg/ml (p<.0001) (197). Support comes from two positive studies (185, 194) and a third which showed that TNF-a response to endotoxin stimulation is abnormally reduced in CFS patients (190). The only negative study merely showed no significant increase in TNF-a among CFS patients (189).

The third cytokine which seems consistently abnormal is interleukin-6 (IL-6). Six reports show a significant elevation in CFS patients (184, 192, 194, 195, 196, 197) while only two could detect no significantly elevated IL-6 levels in patients (185, 189). Please note that McDonald et al?s 1996 study found none of four tested cytokines elevated in 47 patients compared to 47 controls (189). This is the only totally negative study of cytokines that I found.

Several other cytokines have sufficiently consistent reports of elevated levels to impress that they may be significantly abnormal in CFS patients. Interleukin-1, both alpha and beta have been found elevated (184, 185) and its response to both endotoxin and physiologic stimulation has also been found to be abnormal (190, 193). Only McDonald disagrees. Interleukin-2 is elevated in two series, in one was abnormal in 15.6% of cases (185, 187) Another study found normal IL-2 levels (188). Transforming growth factor-beta (TGF-b) was one of the first cytokines to be identified as abnormal in CFS (182, 191) and again McDonald et al. disagree.

We find scattered suggestions that there may be other cytokine abnormalities in CFS. Other reports note elevated C-reactive protein and beta-2 microglobulin (192), alpha-2 macroglobulin (195), IL-2 soluble receptor (185), IL-1 soluble receptor (193), and IL-1 receptor antagonist was high in the follicular phase of the menstrual cycle in patients tested by Cannon et al. (193).

Although these data give strong evidence that the immune system is activated, or ?up-regulated? in CFS patients, no authors would state that these tests are in any way diagnostic for CFS. Please note that even in the most positive series with a strong statistical significance of p<.0001, only 32% of CFS patients tested had a positive result (197). In two publications, the authors note correlation of abnormal test results to severity of symptoms (185, 186), another can associate elevated IL-6 with fever patients (192). No other groups can make any correlation of cytokine levels with severity of illness. These reports encourage further study of the immune system but cannot solve our puzzle.

Animal model of CFS testing the cytokine paradigm

Sheng and co-workers from Minnesota injected 2mg of Corynebacterium parvum antigen into mice of two different strains and measured daily running distance (pre and post-injection) to determine fatigue (198). One strain, C57BL/6 mice showed a significant reduction in running activity. Injection of antibodies specific to either IL-1b or TNF-a did not alter the apparent fatigue. It was found, however, that in the brains of the fatigued mice the expression of both TNF-a and IL-1b mRNA were increased. The elevated CNS cytokine mRNA expression corresponded to the development of fatigue. Once again, we are involved with the central nervous system. The road to knowledge about CFS usually goes in circles.

Studies of cellular markers and function.

All of these cytokines are telling us that the immune system is activated. Now we ask which cells or systems are involved? Plenty of work has been done and the results are again complicated and conflicting. Researchers choose to study different aspects of cell function. Each is selecting from the menu of tests according to their tastes and abilities. Because of their diverse approaches, data are diffuse. Guided by the good reviews of Evengard (135), Bell (110), Gordon (199) and through literature search, we will consider a group of 18 works which make more sense taken as a corpus than individually (200-217).

Reduced natural killer (NK) cell function is the only abnormality that is consistently reported (200, 202, 206, 216) with a fifth study showing abnormal failure to increase NK cell activity following L-arginine stimulation compared to controls (215). Evengard cites an additional six reports all in agreement that NK cell function is reduced in CFS patients (135). Only Mawle et al. from the CDC show no significant decrease (211). This study does for cell data what McDonald?s did for cytokines: It is the only report which is totally negative.

Evengard notes that four publications have documented abnormalities in T-cell responses to stimulation (135). Responses to mitogens and specific antigens have been depressed. This seems to be a reliable trend.

There are abnormalities which may be significant across all of these studies. ?Naïve? T-cells (CD4+CD45RA-bearing cells) are generally decreased(202, 205, 207) with one normal report (214). Adhesion markers (CD39, CD54, CD58) are a sign of activation. They are reportedly increased (205, 207) or ?slightly increased? (211). Two early studies showed a decreased T-helper to T-suppressor (CD4+/CD8+) ratio (202, 205). They?ve got to get easier names for these cells!

A peculiar phenomenon is now noticed. A number of measures of cell function have been demonstrably abnormal in the first report or two and subsequently have been quite normal in no less than two studies. Without the chronology, it simply seems we have conflicting data. These measures include: CD38 ?activation antigens? ( elevated 204, 207 vs. normal 210, 212, 214), HLA-DR histocompatibility antigens ( elevated 203, 204 vs. normal 210, 214), circulating immune complexes (elevated 208 vs. normal 211, 214), CD16+ and CD56+ NK cells (decreased 207, 208 vs. elevated 212 vs. normal 214, 216) and the immunoglobulins IgG (reduced 201, 202 vs. elevated 208 vs. normal 209, 211, 214) and IgA (decreased 200 vs. increased 208 vs. normal 209, 211, 214). I find no explanation for the consistent progression from abnormal to normal of these reports of seven different aspects of cell function. Perhaps we are dealing with random variation? If so, it is doubtful that they have meaning to us.

Vedhara et al, have tested immunological function in CFS patients in a novel way. They randomly allocated live poliovirus vaccine or placebo to 14 CFS patients and compared them to each other and to 9 healthy controls who received the vaccine (218). They found evidence of altered immune reactivity and virus clearance. They found increased poliovirus isolation, earlier peak proliferative responses, lower T-cell subsets on certain days and a trend for reduced gamma-interferon. No symptoms of CFS were exacerbated.

Cell-mediated immunity has been tested. Evengard cites Lloyd et al, who in 1992 found reduced cell immune competence (135). Two later reports contradict this, showing intact delayed hypersensitivity (DH) to childhood vaccines (219) and no difference in DH in a controlled study at the CDC (211). Lloyd?s group, who had found reduced DH in ?92 reported in 1995 that cell mediated immune function, measured at trial entry and follow-up in 103 patients, was unchanged and had no effect upon outcome (220). Cell mediated immunity is not a significant factor in CFS.

Evidence for autoimmune activation

In discussing autoimmunity in CFS, we are dealing with a gray zone. If a patient is positive for a defined autoimmune disease then by definition, she is not a CFS patient. For example, a strongly positive ANA moves the diagnosis away from CFS to systemic lupus (SLE), one of the NIH?s diagnoses of exclusion (55). Nevertheless, with so much evidence for immune system activation, it is of considerable interest to investigate autoimmune reactivity.

About ten years ago I stopped routinely testing my chronically fatigued patients for anti-nuclear antibodies (ANA) to rule in or out SLE. I had found that many were positive but at such low levels (usually at 1:40 to 1:160 titer) that my rheumatologist consultant felt nothing needed to be done. Similar findings are skillfully reported by von Mikecz et al. (221). They found that in 60 patients with CFS, 68% had a positive ANA and 47% were positive to cytoplasmic antigens. Overall, 83% of CFS patients had at least one positive for these two antigens, significantly more than the 17% recorded in their control group.

Other investigators report positive anti-serotonin antibodies along with weaker reactions to anti-gangliosides (seen in Guillain-Barre) and anti-phospholipids, the later two not evidently significant for CFS or FM (51). Plioplys found no anti-muscle or anti-CNS reactive autoantibodies in ten patients compared to ten controls (222). This was a very small group. Finally, Berg et al. suggest that CFS and FM are variants of antiphospholipid syndrome (223). They suggest using a panel of five tests of coagulation activation but offer no results. The authors seem to me overly optimistic, yet if they are correct, we can close the book on CFS.

Hashimoto?s autoimmune thyroiditis is common in allergic patients. This diagnosis and it?s implications to CFS will be discussed in depth later in this review. Insulin resistance and adrenal insufficiency may be linked also to autoimmune processes, to be discussed subsequently.

As a final brain teaser before we leave the autoimmune arena, let?s consider autoantibodies to neuronal proteins. In a wonderful review, Vincent et al. remind us of myesthenia gravis with its anti-acetylcholine receptor autoantibodies, then edified me with data about other similar conditions (224). Lambert-Eaton myasthenic syndrome (LEMS) is caused by autoantibodies to the P/Q voltage gated calcium channels (VGCC). It is associated with significant autonomic dysfunction (225) which may have some relevance to CFS patients. Furthermore, LEMS IgG has been shown to reduce hormone release in rats from both anterior pituitary cells and insulinoma cells, though this was not found in a small human study (226). This also could have relevance to CFS patients. A substantial minority of these patients are autoantibody negative upon testing (224). This is a tough one to diagnose!

Vincent discusses the fact that the CNS is protected from autoimmune diseases by the blood-brain barrier (BBB). Having mentioned anecdotal reports which suggest that in certain circumstances the BBB may be breached, she raises the possibility that cytokines or other circulating factors could cause these disturbances (224). It seems that the activated immune system may effect the CNS in many ways.

Apoptosis, RNase L and interferon-induced proteins.

Apoptosis is a form of cell death initiated by extracellular or intracellular signals in which enzymes in the IL-1 family are activated to degrade nuclear DNA, causing the cell to shrink and finally break up. In the immune system, this process is used to delete autoreactive lymphocytes . I had to look that one up. Swanink et al. found no increased apoptosis in leukocyte cultures from 76 CFS patients compared to 69 healthy controls in 1996 (210). Vojdani et al., in a smaller group of 29 patients studied peripheral blood lymphocytes and found increased apoptotic cells compared to 15 controls (227).

Suhadolnik et al. have a series of papers documenting significant dysregulation in several components of the 2?,5?-oligoadenylate (2-5A) synthetase/RNase L and PKR antiviral pathways in CFS (227a). Various subsets of patients are described. He ends with the splendid observation that the RNase L enzyme dysfunction in CFS is more complex than previously reported. Agreed. Interestingly, this work is well supported by two papers from Vojdani?s group (226, 228).

Allergy and chronic fatigue

The interconnection of allergy and chronic fatigue is very apparent to the Otolaryngic allergist. Although the high rate of allergies in CFS patients has been repeatedly noted, running 66% to 83% (189, 229, 230, 231), with increased nickel sensitivity (231) and activation of eosinophis causing elevated serum eosinophilic cationic protein are reported (229), relatively little is made of this association. Borish et al. have used PCR to find that cytokines (TNF-a) in peripheral blood mononuclear cells are similarly and significantly elevated in both CFS and allergic patients (230). They also found a significant decrease in IL-10 (230). They proposed that allergic inflammation could produce CFS symptoms in susceptible individuals.

A number of papers suggesting a link between allergy and fatigue appeared as early as 1928 (232, 233, 234). These generally cite food allergy as the causative agent. This was not received with enthusiasm by the IgE ?purists?, who had hoped to hear the last of Coca and Rinkle?s ideas about food sensitivity (235). The schisms in the community of allergists which led to the formation of what are now the American Academy of Otolaryngic Allergy in 1941, the American Academy of Allergy, Asthma and Immunology in 1942 and the American Academy of Environmental Medicine in 1963 broke upon this issue (235).

Persistent limitation of the concept of ?allergy? to IgE-mediated type I Gel and Coombs reactions hinders our colleagues. Expanding the definition of allergy to include all four major Gel and Coombs pathways opens broad avenues of research and therapy.

Treatment based upon an immunological paradigm

Terfenadine did not benefit a small group of 28 CFS patients (236). This condition is not a simple IgE-mediated problem, despite the high percentage of allergic patients in the group. An aggressive trial studied 99 CFS patients in a double-blind, randomized, placebo-controlled trial of intravenous immunoglobulin (237). It did not help patients. Adverse reactions were reported by 70% of patients. This suggests that in these patients, CFS symptoms do not have a significant autoimmune component. Strayer et al?s study of Ampligen has previously been noted (176).

Transfer factor (TF) has been used to treat CFS patients. Transfer factor is an active component of dialysates of human leukocyte extracts. It can transfer antigen-specific DH and cell mediated immunity as well as enhancing T cell responses to mitogens and increasing the percentage and total numbers of circulating T cells and T helper cells (238). Three studies of TF and a review article were published in a single issue of Biotherapy in 1996 and I can find none since (239 – 242). Of these, a Czech study of 222 patients was most ambitious. This open treatment trial showed that older patients (aged 54 – 77) fared less well with treatment than did two younger subsets (241). Rea and co-workers at the Environmental Health Center in Dallas have considerable experience with TF, largely reporting good results as a maintenance rather than a curative treatment (238).

Summary

Many immunological abnormalities have been well documented among CFS patients. Of these, the single most commonly reported finding was allergy, uniformly seen in the majority of patients. It is safe to state that CFS patients have a significantly activated, or ?overactive? immune system compared to healthy controls. These data support CFS an a clinical entity but cannot be considered diagnostic for CFS.


Fungal hypersensitivity theory, or ?candida related complex?

The ?yeast? hypothesis is related to the allergic and immunological rather than to the infectious paradigm of CFS. This crucial concept is generally not understood. This misunderstanding has relegated a valid component of the CFS patient?s total load to the realm of medical counter-culture. Kroker?s virtuoso review of the medical literature and explanation of this syndrome is on my ?must read? list for anyone serious about treating CFS patients (243).

As an analogy, imagine an asthmatic patient going to an allergist?s office and complaining of wheezing all night long. The allergist tests the patient and finds her highly allergic to cats. Hearing this, the patient says: ?Oh, no; three cats sleep on my bed all night!? What doctor would fail to tell the patient to put the cats out of the house? The ?yeast? question is a similar issue, involving the body?s internal environment rather than the outer environment of the bedroom.

The proposed mechanism of the ?yeast connection? is an infestation of the gastrointestinal (GI) tract with an allergenic fungus. Symptoms are caused by an immune response to the fungus in the gut with consequent inflammation of the gut mucosa and by immune responses to various circulating fungal and other antigens (including foods) that are absorbed through the inflamed and ?leaky? gut mucosa. Type I, III and IV immune responses are involved (243). The issue is neither infection nor parasitization but rather allergy and hypersensitivity.

The recommended treatment is the elimination of this fungus from the gut. Because of rapid fungal growth rates, this may be difficult to accomplish. A well-known protocol is recommended by Crook (244). The four arms of the regimen include: A low carbohydrate diet, antifungal medications, probiotics (beneficial normal GI flora like Lactobacillus acidophilus), and high potency vitamins and nutritional supplements. This is a treatment trial. If it fails to help substantially, it ought to be abandoned after two weeks.

In my experience, the treatment usually helps selected patients. The protocol works in many ways, though, beyond simply eliminating fungus. The low carbohydrate diet not only ?starves? the yeast into a slower growth rate, it mitigates symptoms of hyperinsulinemia which will be discussed later. In addition, it is an oligoantigenic diet which removes common allergens like milk, chocolate, fruit and mold in addition to preservatives and artificial sweeteners. Patients must prepare their own meals using fresh or frozen foods. Without fast food, canned foods, ?junk food? or sugar, patients eat healthier, more nutritious meals. The recommended vitamins and supplements provide antioxidants as well as improving access to important nutrients like B vitamins, essential fatty acids and minerals. This is consistent with Pauling?s suggestions for optimal rather than minimal required daily intake of vitamins (245).

Normal bacterial flora may play a significant role in gastrointestinal homeostasis (246, 247, 248). Kroker cites Bolivar and Bodey?s work showing that broad spectrum antibiotics alter the flora and permit overgrowth of fungus (243). The repeated use of broad spectrum antibiotics is felt to be instrumental in the genesis of the yeast problem. Oral supplementation with normal gut flora is believed to combat the growth of the fungus. In replenishing the gut bacteria, the treatment also restores any benefits of a healthy gut ecology.

Antifungal medications are an important part but by no means the only part of this complex regimen. Kroker discusses a variety of antifungal treatments, both pharmaceutical and ?natural?, both systemic and non-absorbable. With emerging fungal resistance against these agents, at least one reference laboratory offers stool fungus culture and sensitivity panels (249).

Unfortunately, only one blinded prospective study of the yeast hypothesis has been published (250). In this negative trial, the single intervention studied was oral Nystatin vs. placebo. All other aspects of the recommended treatment were omitted, presumably to limit the otherwise large number of variables. From this data we can state that the use of Nystatin alone is not an adequate treatment for these patients. The authors do not convincingly support their claim to have invalidated the ?Candidiasis Hypersensitivity Syndrome?. Conversely, only anecdotal evidence supports the continued use of this protocol for chronically fatigued patients (251).


Neurally mediated hypotension and dysautonomia

Hypotension is rarely considered a pathological disease state by practitioners in the Western world (252). Indeed, it may be difficult to identify patients with episodes of markedly low blood pressure. Bou-Holaigah and colleagues from Johns Hopkins review the many synonyms and the proposed mechanism of action for neurally mediated hypotension (NMH) expressed as syncope and near-syncope in their important study from 1995 (253). These episodes of hypotension are thought to result from a paradoxical reflex initiated by venous pooling on prolonged standing. This causes reduced ventricular preload. Susceptible persons then produce high levels of catecholamines. These augment inotropism and excessively stimulate mechanoreceptors within the left ventricle of the heart. This mechanoreceptor activation then causes withdrawal of sympathetic and increased vagal tone. This in turn causes vasodilatation, bradycardia and syncope or near-syncope. Following such an event patients remain fatigued for a surprisingly long time.

Wilke et al suggest a more complex set of possible ourcomes in addition to the above, which they term a (1.) vasovagal reaction. These include: (2.) ?Vasodepressor reactions? with suddenly decreased BP but increased HR, (3.) Progressive orthostatic hypotension with or without altered HR, (4.) Orthostatic tachycardia alone and (5.) ?Chronotropic insufficiency?, in which the BP changes normally but the HR remains unchanged (254). These authors agree that fatigue may be significantly associated with these events. This large number of possible responses makes comparisons between series of patients in the medical literature more difficult.

The first reports of testing CFS patients with the tilt-table came from Rowe, Bou-Holaigah and colleagues at Hopkins in 1995 (253, 255). Reviewing relevant literature, they support the observations that the symptoms of CFS and NMH overlap to a great extent. They propose that some CFS patients actually suffer from NMH.

They then validate the head up tilt-test as a measure of NMH in a literature review. Combining published data, they note that approximately 50% of patients believed to have NMH and only 8% of controls will demonstrate an abnormal response to upright tilt testing. The reproducibility of tilt-testing ranges from 77% to 90%. Adjunctive use of isoproterenol to augment the subject?s own catecholamine production increases the rate of positive tests to 65% of NMH patients and 27% of controls. The authors advocate its use, even though this infusion disproportionately increases the rate of false positives from 8 to 27% (a change of 19%, or 2.37-fold increase) while improving the true positive rate only from 50 to 65% (a 15% change or 0.3-fold increase) (253).

The Hopkins group?s first report showed that all in a group of seven adolescent patients, four of four with CFS and all three with ICF, had significant hypotension on tilt-testing (255). In the same year their most significant series was published. Twenty-three unselected CFS patients were tested and compared to 14 healthy controls. All patients complained of symptoms and increased fatigue on tilting compared to none of the control subjects (P<.001). Sixteen (70%) with CFS became hypotensive with upright tilt compared to none of the controls (P<.001). With isoproterenol intravenous infusion, 22 of 23 (96%) of CSF but only four of 14 (29%) healthy subjects had abnormal responses (253). All of the patients? abnormal responses conform to Wilke?s vasovagal category (254).

A number of similar patient series have subsequently been reported and few yield such strong evidence. In order of decreasing frequency of abnormal patient response, these positive studies show: Five of 5 (256), eleven of 15 (73%) vs. 0/15 controls (257), fifty-two percent of 71 patients including 17 (24%) vasovagal and 20 (28%) orthostatic tachycardia responses (258), Thirty of 75 (40%) patients vs. 8 of 48 (17%) controls (259), Twenty two of 78 (28%) (260) and five of 20 (25%) (261). Totaling these positive series, we find 110 abnormal responders among 264 CFS patients studied. This gives a combined positive rate of 42%.

There are moreover, three principally negative tilt-test series. In one, 11/39 CFS patients and 12/31 controls reacted abnormally (262). Only heart rate was found significantly higher in the CFS group. The second study measured only HR variability in 19 CFS patients and 11 controls and found none (263). The third found no differences between 21 CFS and 13 controls in most measures with only the post-test heart rate (P<.01) and low frequency power (P=.02) found significantly higher in CFS patients (264).

It is doubtful that NMH could be the sole cause of CFS, though CFS certainly seems to be associated with hypotension. The physiologic changes in CFS patients which have been associated with NMH may arise from different sources. More information comes from treatment trials to be discussed below.

Dysautonomia

Entertaining the hypothesis of neurally mediated hypotension, we must consider the possibility that chronic fatigue syndrome is caused by an idiopathic autonomic neuropathy. Studies of tilt-table testing measure parameters associated with autonomic function. Autonomic parameters in CFS patients have been studied using other methods. Blood pressure and heart rate while at rest, in performing various tasks both physical and mental and for 24 hours? ambulation are studied (265, 266). Neither group found any significant autonomic abnormality.

Electrocardiographic (ECG) R-R wave interval variability has been tested in two roughly comparable studies with conflicting results, one showing more variability in CFS (266, 267). Results of paced breathing have also given inconsistent results (265), A treadmill test of eleven CFS patients showed significantly reduced vagal power compared to controls (268). Even the simplest measurement of heart rate at rest has been inconsistently reported, with three groups finding that CFS patients have higher resting HR (261, 262, 266) and four stating that there was no difference between patients and controls (253, 263, 265, 269).

With such variability in even the most basic vital sign, it is no wonder that there is profound disagreement between the authors in their interpretations of their data. Two groups state that there is no significant abnormality in autonomic function among CFS patients (265, 266), two others write that vagal power is decreased (267 – 9), two more believe that sympathetic activity is increased in CFS (264, 267) with a third having shown increased plasma nor-epinephrine after standing (257) and one group feels they have shown decreased sympathetic function (261). What disarray!

Treatment based upon the hypotensive paradigm

The Hopkins group designed a treatment protocol to address their NMH hypothesis and used it with good preliminary results, though no follow-up data is published(253). Therapy is designed to increase blood volume through increased salt intake or use of fludrocortisone, a synthetic corticosteroid with strong mineralocorticoid (aldosterone) properties. If needed, a second tier of treatment may be used. The inotropic effects of adrenergic stimulation are decreased with beta-adrenergic antagonists (atenolol) or disopyramide. The bradycardia and vasodilatation of the vasovagal response may be mitigated using anticholinergic antagonists (disopyramide). The specific indications, doses, sequence and some contraindications are given by Wilke et al (254).

Using this protocol, nine of 19 (47%) patients reported complete or nearly complete resolution of all symptoms within one month. Seven more felt at least somewhat better (253). Seven patients were intolerant of some or all of the medications. DeLorenzo and co-workers used a simpler treatment, giving sodium chloride 1200mg daily for three weeks. Of these 22 patients, repeat tilt-table testing demonstrated 11 (50%) no longer hypotensive and reporting improvement of their CFS symptoms (260). Very noteworthy is their observation that those patients who failed the treatment had significantly lower plasma renin activity compared both to the control and successfully treated groups. The authors state that an abnormal renin-angiotensin-aldosterone system could explain both their symptoms and treatment failure.

A novel treatment trial involved application of military anti-shock trousers (MAST) to CFS patients who tested abnormally on the tilt-test (257). Inflation of the MAST during tilting prevented all symptoms. In addition, the group reports finding that while patients have normal circulating plasma volume, their erythrocyte volume is low. Though not proving any particular etiology, this shows that excessive gravitational venous pooling and subnormal circulating erythrocyte volume are very frequent in CFS patients. They may have a role in its pathogenesis. Wilke et al state that venous pooling is an important feature (254). Rowe et al at Hopkins agree, identifying a subset of Ehlers-Danlos syndrome (abnormal connective tissue permitting excessive dilatation of veins) among adolescent CFS patients with orthostatic intolerance (270).

Summary

There is little doubt that about 40% of CFS patients have orthostatic intolerance. Treatment designed to expand circulating blood volume seems to help. Despite a plausible hypothesis of NMH, little evidence consistently supports the presence of autonomic dysfunction. What else could it be?

In a study of 431 fatigued patients, each subsequently diagnosed with one of eight neurological or endocrine disorders, Streeten and Anderson conclude that chronic fatigue is common in delayed orthostatic hypotension and all forms of hypocortisolism but is much less common in the other disorders (271). It is appropriate to discuss Adrenal cortical insufficiency briefly in this context.

Chronic fatigue syndrome shares at least 36 features with Addison?s disease (272). Deficiency of aldosterone may occur with hypocortisolism or in isolation and its symptoms and features also suggest a role in CFS. Hypoaldosteronism may be associated with high renin levels, possibly related to prolonged cortical stimulation (read: ?stress?) (273). Elevated renin has been noted in tilt-test positive CFS by DeLorenzo (260). Investigators of NMH do not report results of adrenal cortical work-up in their patients yet their treatment protocol is fundamentally the same as the medical treatment for hypoaldosteronism: adequate salt intake and fludrocortisone (273).

In summary, CFS patients who are tested using the tilt-table show signs of orthostatic intolerance which might be from autonomic, adrenal or other origin. There is no clear data about their adrenal status. They respond to treatment which is equally effective for autonomic and adrenal disorders. No consistent autonomic abnormalities have been found in multiple studies. It seems that evaluation of adrenal function may be important.


Adrenal and hypothalamic-pituitary-adrenal axis

In his stimulating review article, Clauw comments that the most consistent finding regarding autonomic dysfunction among fibromyalgia patients is an impaired ability to respond to stress (274). Hearkening back to Beard?s claims that the neurasthenic patient?s vital energy had been depleted by stress, we must now consider the primary role of the adrenal glands in metabolic homeostasis and response to stress.

Hans Selye described the association of stress and the activation of the hypothalamic-pituitary-adrenal (HPA) axis with the ultimate result of increased secretion of cortisone from the adrenal glands in the 1930s (6). It is relevant to the study of CFS that Selye suggested that through the chronic stress of a severe disease of any etiology, a patient could present with anorexia, loss of weight, depression, hypogonadism, peptic ulcers and immunosuppression (274). A great volume of work has been produced studying the stress response and is reviewed in remarkably thorough fashion in two review articles by Chrousos and Gold and Heim, Ehlert and Hellhammer and in an excellent book by Rabin (274, 275, 276).

The adrenal gland is composite, having two distinct regions. The center, or medulla is essentially a sympathetic ganglion. This produces adrenaline in times of acute stress: the ?fight or flight? response. This hormone of immediate stress contrasts with the products of the outer part of the adrenal gland, the cortex, which are completely different biochemically and physiologically. The cortical hormones are based upon the cholesterol molecule and therefore called ?steroids?. Of these, cortisol is the most important. It is the hormone of chronic stress and one of the few hormones necessary to sustain life. It will be useful to review the synthesis of steroid hormones, in Figure One.

The HPA regulates production of adrenal steroids. Corticotropin-releasing hormone (CRH) from the hypothalamus and other locations in the brain stimulate release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. The details of this system are not completely defined. ACTH stimulates the adrenal conversion of cholesterol to pregnenolone, which is believed the rate-limiting step in the synthetic cascade. It seems that the fate of pregnenolone may then be directed by need. Increased demand for cortisol may result in diminished production of other steroids. It is well known that stressed women may temporarily stop menstruating. The British have termed the usurpation of sex hormones to produce cortisol ?progesterone steal?. We see that by down-regulating either 17a-hydroxylase or 17, 20 lyase all precursors move towards cortisol synthesis and the sex steroid paths are inhibited.

Heim et al. note some of the beneficial effects of cortisol as the organism is stressed. It induces gluconeogenesis, mobilizes free fatty acids, reduces amino acid use in protein synthesis, increases cardiovascular tone, blood pressure, heart rate, respiratory rate and thus increases overall available energy. In large amounts it reduces immune response in many ways, including lymphocyte function, macrophage activity, antigen presentation, T cell proliferation, natural killer cell function, and cytokine secretion. By inhibiting phospholipase it also inhibits production of various pro-inflammatory prostaglandins and leukotrienes (274, 275). It also restrains growth and reproduction (274). Rabin and Jefferies each emphasize the dose-related nature of immune system alterations by cortisol (276, 277). At usual physiological levels, cortisol enhances normal immune function.

Chronic activation of the adrenals by stress leads to adaptive responses. These adaptations involve various mechanisms. Blood levels of cortisol and tissue cortisol receptor numbers and sensitivity are complexly interrelated (275, 276). Cortisol effects brain CRH secretion and is involved with feedback loops influencing the locus ceruleus-norepinephrine autonomic system, reproduction, growth, several cytokines (IL-1, IL-6 and TNF-a) and the thyroid axis (274, 276). It is noted that some individuals experience maladaptive responses to the detriment of their health.

With failure of adequate counter-regulation, cortisol levels may stay high. What began as a temporary and protective response becomes maladaptive. Arousal transforms into anxiety and vigilance becomes hyper-vigilance and insomnia. Assertiveness becomes excessive caution. The decreased emphasis on feeding and reproduction which is beneficial in acute stress is harmful when stress is sustained. This results in a syndrome of anorexia, hypothalamic hypogonadism and decreased libido characteristic of melancholic depression (274). Studies have demonstrated that lifelong problems may be established early in life and even in-utero (275, 276).

The other significant form of maladaptive adrenal response is hypocortisolism (274, 275). This has been well described in post-traumatic stress disorder (PTSD) patients and also in patients suffering from physical disorders including CFS, FM, chronic pelvic pain, and asthma (275, 278, 279). Hypocortisolism may be a result of simple adrenal exhaustion and chronic decrease in CRH production in CFS patients is clearly demonstrated (278, 279). Responses of both ACTH and cortisol to CRH stimulation are blunted in another controlled series of CFS patients (280). The neuroendocrine correlates of this can be summarized as hypocortisolism and increased feedback inhibition of the pituitary-adrenal level of the HPA axis with apparent hyper-activation of the central CRH system (275). Various glucocorticoid receptor alterations (through adaptations, cytokines or isoforms) may contribute to resistance to cortisol as well (275, 277).

If simple hypocortisolism plays a major role in CFS, how can CFS seem a mysterious illness? The reasons are multiple. First, as observed by Jefferies, adrenal cortical insufficiency has come to be viewed exclusively as it?s most severe manifestation: Addison?s disease. Nowhere in current texts do I find a discussion of a borderline deficiency state or description of a syndrome of inadequate adrenal functional reserve (273, 281, 282). Harrison?s 7th edition in 1974 defined adrenocortical hypofunction as ?all conditions in which the secretion of adrenal steroid hormones falls below the requirements of the body? (283). This definition was accurate in it?s lack of specificity but it has been deleted in the 14th edition which defines the condition strictly by an abnormal ACTH stimulation test result (273).

The second reason, then, is the difficulty in accurately testing the function of the adrenal gland. Unlike the thyroid gland, which stores a large amount of hormone and has relatively little diurnal variation in output, the adrenal stores no hormone but releases it promptly upon synthesis. Further, there is a strong diurnal variation and even hourly pulsatile fluctuation in ACTH release and cortisol synthesis (277, 281). Tests for ACTH and cortisol blood levels must then be done with an eye on the clock and the patient?s sleep pattern. A blood test shows only the blood level at the moment that the needle has pierced the vein. Also, published ?normal? values may give an excessively broad range (284). Williams and Dluhy state that plasma cortisol values in Addison?s patients vary from zero into the lower range of normal; therefore some patients will have normal blood cortisol levels despite their disease state (273). Urine free cortisol is thought by some inaccurate because the detection limit of the assay lies in the normal range of cortisol excretion (281). Because of these difficulties, the standard diagnostic test for adrenal insufficiency is designed to measure adrenal response to ACTH stimulation.

As originally performed, the ACTH stimulation test required 8 hour continuous drips of ACTH daily for 4 or 5 days, during which time consecutive 24 hour urine specimens were collected for measurements of creatinine, 17-hydroxycorticoid and 17-ketosteroid levels (283). The inconvenience and expense of this protocol is amazing, necessitated by insensitive laboratory tests of the early 1970s. It is very important to note that this 1974 text mentions ?incomplete adrenal insufficiency? as a variant test response. These patients responded with small increments in steroid excretion on the first 3 days of the 5-day infusion test then on the last 2 days there was an actual decline in the level of steroids. The authors state ?these results suggest that the limited adrenal tissue has been maximally stimulated and has insufficient steroid reserve capacity?. This contention is well supported in my clinical experience with CFS patients.

With the development of superior assays, the ACTH stimulation test has been abbreviated to a single intravenous or intramuscular injection of ACTH with measurement of cortisol before, at 30 (or 45) and 60 minutes later. If the serum level of cortisol exceeds 20 mcg/dL, the result is considered normal by some (281). Others require a stimulated cortisol level of at least 18 mcg/dL and a minimal stimulated increment of more than 7 mcg/dL (273). For the CFS patient, this test is inadequate. Many CFS patients will relate that they felt well for a few hours after this test then ?crashed? and suffered significant exacerbation of their CFS symptoms for many hours afterward. Clearly, something had been missed. Other testing is needed.

Understanding that hypocortisolism in CFS patients may be accompanied by an inhibited HPA axis, depressed ACTH release, glucocorticoid receptor resistance and blunted response to ACTH stimulation as above, it is understandable that a single test may not suffice. Salivary assays have been studied with mixed results perhaps due to estradiol effects on cortisol binding globulin (275, 285, 286, 287). A low dose ACTH test using not 250 mcg but 1 mcg of ACTH designed to detect subtle abnormalities does not fully meet expectations (288, 289).

The single most useful test for my patients has been a 24-hour urine assay using GC-mass spectroscopy technique. This is available through the Mayo Clinic and Meridian Valley Clinical Laboratories in Kent, Washington. The second laboratory gives more data at a lower price, that includes free cortisol, cortisone (a less active pre-hormone, as T4 is to T3), aldosterone, two precursors (pregnenolone and DHEA) and two metabolites (etiocholanolone and androsterone) along with creatinine and total volume. When combined with routine blood tests for progesterone, testosterone and estradiol as indicated, a very complete picture of steroid hormone synthesis is realized. Urine testing may be very sensitive if ?renal sparing? exists for steroid products. Re-uptake by the kidney maintains normal blood levels longer during times of shortages – an economy measure. If in effect, this would mean that urine levels would decline considerably earlier than blood levels and allow earlier diagnosis of declining production.

This method may be used for a 24-hour urine ACTH-stimulation test. It is particularly worthwhile to note the responses of the precursors and metabolites as well as of the cortisol. Many CFS patients will actually demonstrate a decrease in cortisol production after stimulation. This seems to demonstrate decreased adrenal functional reserve and may correspond to the 1974 observations cited above (283). This is termed ?the stumbling runner phenomenon? by Jonathan Wright (personal communication). Imagine running in a footrace as fast as you are able. If you are then whipped, you cannot run any faster and the distraction may cause you to stumble. This seems to be an adequate metaphor for the above phenomenon.

There remains the unanswered question of receptor resistance. Is the cortisol in the blood and urine normally functioning at its receptor? It is interesting to consider testing two other endocrine glands, the thyroid and the endocrine pancreas as we test the adrenal. Would we be content to be told that no matter a patient?s baseline TSH, there was no disease as long as her thyroid hormone level rose into the normal range following a strong stimulation with synthetic TSH? Now imagine a test for diabetes which monitored insulin response to a glucose challenge which was interpreted as normal if the insulin rose by 50% or more of its normal resting value. It would be a highly specific test for patients with hypoinsulinemic diabetes mellitus but would miss the whole cadre of insulin-resistant patients, a much larger group. We do not have a perfect test for adrenal gland sufficiency to meet the requirements of our CFS patients.

The third reason for adrenal dysfunction remaining under-diagnosed in CFS patients revolves around many treatment issues (277). Following the therapeutic fiascoes of the 1950s, both physicians and patients are afraid of all steroid hormones. Synthetic hormones are usually employed now, and may not well replace the patient?s adrenal steroid deficiency. Most important, though, is the tendency to over-treat. Patients may be given too much hormone too fast and they can?t handle it. Consider that the normal adrenal cortex daily produces about 20 to 30 mg of cortisol (called by pharmacists ?Hydrocortisone?, another source of confusion). This is equivalent to about 5 mg of Prednisone and 4 mg of Medrol – not too darn much. The physiological requirement for cortisol is therefore quickly exceeded and the adrenal gland suppressed when using synthetic glucocorticoids. Recall that the patient will have been relatively deficient for a long time. Just as one slowly and carefully escalates thyroid hormone replacement therapy in a myxedematous patient, one needs to gradually build the cortisol dose in a CFS patient. Finally, fludrocortisone is a mineralocorticoid and may not meet glucocorticoid requirements in a patient with hypocortisolism.

Several reports seem to substantiate the foregoing. Gordon cites a 1989 trial of glucocorticoid treatment which showed no positive and some deleterious results (199). Fludrocortisone is helpful when given to CFS patients with postural hypotension (vide supra). A small blinded trial giving 0.1 to 0.2 mg fludrocortisone to unselected CFS patients was disappointing, however (290). A report in 1998 claimed to employ a low-dose of hydrocortisone but actually gave suppressive doses. Patients showed significant improvement on treatment without significant adverse symptoms but 12 of 30 taking hydrocortisone showed suppression of glucocorticoid responsiveness (291). Jefferies summarizes work reporting good symptom improvement in truly small, ?sub-replacement? (or sub-suppressive, sub-physiological) doses of hydrocortisone (277). In a truly low-dose controlled treatment trial giving 5 mg or 10 mg daily to 32 CFS patients there was significant improvement with treatment without suppression (292).

A fourth set of reasons for the lack of recognition of adrenal involvement in CFS is the complexity of associated abnormalities. From the discussion above, it is clear that psychiatric symptoms are associated with cortisol dysregulation. The clinician accustomed to treating CFS patients will not fail to notice the importance of the fact that Addison?s patients have increased incidence of autoimmune thyroiditis (both hypo- and hyperthyroidism), premature ovarian failure and type I diabetes mellitus (273, 281). Increased association of hypocortisolism with vulnerability to asthma, allergies and autoimmune disorders is clearly significant (275). These are compounded by ongoing stress, which alone will decrease TSH production and inhibit conversion of low-potency T4 to high potency T3 (274). Add into this mix the effect of ?progesterone steal? and imbalances in the delicate monthly fluctuations in the menstrual cycle and it is understandable that simple treatment with even the most perfect dose of hydrocortisone will not restore a CFS patient to full health in the few months? time used in most studies.

Future treatment for this problem will include steroid precursors, DHEA and pregnenolone, which are already getting attention in world literature (293 –297). I have found these very useful tools in my practice for over five years. It is most useful to use them in conjunction with a nutritional supplement designed to supply the co-factors for the cortical synthetic enzymes. These allow the hormone precursors to move smoothly through the pathways, as clean oil lets the automobile engine run smoothly. Some patients need only this ?glandular? support.

Summary

The most consistent finding among CFS patients is their inability to normally respond to stress. The HPA axis is of prime importance in the adaptive response to stress. Major stressful events or repeated smaller stresses may lead to maladaptive responses which can result in adrenal cortical insufficiency. This produces a plethora of symptoms and indeed there is much overlap between symptoms of CFS and Addison?s disease, the most severe adrenal disorder. The diagnosis of the role of adrenal cortical insufficiency is more difficult because of the complexity of the neuroendocrine pathophysiology, the types of testing commonly employed and our peculiar conceptualization of adrenal insufficiency as an all-or-none phenomenon. Successful treatment may be accomplished by judicious use of small doses of supplementary hormones and nutrients. Results will be best when associated disorders are also treated. Three of these, ovarian dysfunction, insulin resistance and thyroid dysfunction are importantly, even inextricably interrelated with the adrenal.


Ovarian dysfunction and polycystic ovary syndrome

In a conversation recently overheard, a woman confessed the desire to purchase a Jaguar automobile. Her friend laughed and said that she had better first get married to a mechanic. In fact, the woman already owned the endocrine equivalent of a Jaguar: ovaries. These glands are ?fearfully and wonderfully wrought?: In health they produce in predictable ratios the hormones progesterone, testosterone and three estrogens. They respond to a complex interplay of positive and negative feedback to vary hormone production in a constantly fluctuating pattern for over thirty years. This doesn?t even mention their role as repository and training center for the ova or their ability to totally alter their function during pregnancy. As shown by the Jaguar, the more complex and finely tuned a mechanism, the more likely it is to get out of order.

There are a variety of insults which impair normal ovarian function. Foremost of these is stress. It is well known that highly stressed women may temporarily stop menstruating. This may occur with hypercortisolism. Hypocortisolism is the other maladaptive response to chronic stress and is also associated with conditions known to interfere with the menstrual cycle. These include adrenal insufficiency, hypothyroidism and CFS (298).

It seems that rather than simply being casualty of disease, the ovarian imbalances may play an active part in the production of symptoms in CFS patients. The association between CFS and menstrual problems has been noted comparing 150 patients to 149 controls (299). Diverse works predating the formal definition of CFS such as Crook?s The Yeast Connection and Saifer?s ?APICH syndrome? make a strong connection between ovarian symptoms and chronic fatigue (244, 300).

Dalton?s pioneering work with premenstrual syndrome (PMS) in Britain in the 1950s called attention to the role of steroid sex hormones in both physical and mental health (301). A great amount of practical experience in hormone use and familiarity with side-effects was gained with the advent of the oral contraceptive pill (OCP) and post-menopausal hormone replacement therapy (HRT). In addition to the clear physical advantages, the psychotherapeutic benefits of estrogen treatment on both depression and cognitive functioning are now well accepted (302).

The controversy about post-menopausal hormone replacement therapy is elaborated by physician authors of popular books (301, 303, 304, 305). Each advocates the advantages of proper HRT, though their methods are diverse. It is apparent that imbalances between the steroid sex hormones may cause many symptoms, as in PMS. It is also clear that changing hormone ratios cause many symptoms in the ?perimenopausal? woman. A substantial number of CFS patients are perimenopausal women. As these CFS patients are effected by these fluctuating hormone ratios it may be useful to evaluate the steroid sex hormones.

Progesterone plays a central role in this drama. Its deficiency relative to estradiol produces symptoms usually described as ?estrogen dominance? summarized in table five (303). Progesterone is both a hormone and a precursor of cortisol. As noted, it may be usurped by the adrenal under stress, creating a relative imbalance. As the patient enters her fifth decade, this may become more noticeable with diminished ovarian production and therefore increased demand upon the adrenal gland. Progesterone supplementation, sometimes in prodigious doses, is recommended by some authors as a cure for many perimenopausal symptoms including fatigue (301, 303). This progesterone may supplement adrenal production of cortisol as well.

When indicated by history and symptoms, assays for three steroid sex hormones, progesterone, testosterone and estradiol give useful information about the female CFS patient. When specimens are collected in mid-luteal phase of a menstruating woman, about the 20th day of the cycle, blood tests for these three hormones are strikingly consistent with the 24-hour urine adrenal steroid profile results. Combining these tests, the clinician notices the integral connection between the adrenal and ovarian hormones.

The problem of synthetic steroid sex hormones must be mentioned. They cannot be measured. It seems peculiar to prescribe a hormone for which the blood levels cannot be measured (imagine doing so with thyroid hormone) yet this is often the case. The estrogenic compounds in the OCP and some equine estrogens in Premarin are too different from human estrogens to be detected by standard blood tests for estradiol (305). The presence of many estrogenic chemicals in the environment has been repeatedly mentioned in the popular press and these may add to our estrogenic exposure (303, 306). None of them are measurable as estrogens. Progestins like Provera and agents in the OCP are also invisible to laboratory assays for human progesterone. Many CFS patients will come to the clinic taking synthetic hormones and potentially significant imbalances may be difficult to detect.

Polycystic Ovary Syndrome

Polycystic Ovary Syndrome (PCOS) is increasingly of interest to clinicians (307). The syndrome is remarkably common, with an incidence of up to five to 10% of all women. It has been popularized by the press as ?Syndrome X? (308). The most comprehensive review is by Dunaif (309). These patients are often chronically fatigued. Overlapping features in CFS and PCOS have been noted (299, 310). Characteristically, serum insulin levels are elevated (311). This is the principal underlying disorder causing the syndrome (307).

Consequences of hyperinsulinemia include excessive production of androgens (not always testosterone) from increased ovarian stromal hyperthecosis, causing acne and hirsutism. An abnormality of particular interest is reduced sex hormone binding globulin (307). This means that a test for ?total testosterone? may fail to reveal the patient?s elevated unbound testosterone, which is the biologically active form. The most accurate test is for ?free testosterone?. Standard laboratory tests for progesterone and estradiol are also tests of total hormone so their results may also be inaccurate in PCOS patients. Testing 24-hour urine samples or saliva samples may be valid alternatives to blood tests. Though these reflect levels of free hormone, one must recall that they are excretory tests effected by total production of hormone as well as blood levels.

While muscle and adipose cells are insulin resistant, the ovaries may have increased insulin sensitivity. Most patients have menstrual irregularities, usually starting with menarche. They have imbalanced LH and FSH (hyperprolactinemia) and are often infertile. Many patients are obese, at least partly due to the effects of insulin resistance. The frequent finding of elevated cholesterol is also related to high insulin (307). Insulin has an aldosterone-like effect on renal function and may contribute to hypertension (312). These effects act synergistically to create at least a seven-fold increased lifetime risk of myocardial infarction and equally increased risk for diabetes mellitus (307). As this syndrome responds well to treatment, it is obviously important to make an early diagnosis.

Dunaif astutely comments that the inherent bias in studies of PCOS is the use of polycystic ovaries as a diagnostic criterion (usually by ultrasound). Not all syndrome patients will express all features of the disorder, including polycystic ovaries. Family studies show that beyond an increased incidence of PCOS in female relatives of patients, some brothers also are insulin-resistant (308). The association of men and this disorder conceptually links PCOS and CFS with the syndrome of insulin resistance.

Summary

Ovarian hormone imbalances and their consequent symptoms are common in women with CFS. These may be secondary to the same stress which seems to precipitate CFS or simply to the stress of being sick with CFS. The interrelation between the ovarian and adrenal hormones is readily apparent. Insulin receptors in the ovaries may be overly activated to further complicate clinical symptoms. It is possible that ovarian pathology and the imbalance of the steroid sex hormones may be a primary contributor to the clinical picture of CFS.


Insulin resistance and hyperinsulinemia

Insulin resistance without diabetes mellitus may be of considerable importance in patients who are chronically fatigued and even with CFS. Does insulin resistance cause CFS? Academically the answer is ?no?, for then the patient would have insulin resistance, not CFS. Clinicians, though, may be well alerted to the possibility that insulin resistance and hyperinsulinemia are importantly associated with CFS. A number of investigators have studied parameters directly or obliquely associated with insulin resistance. These studies validate our attention to symptomatic insulin resistance in the context of CFS.

In controlled studies, Allain et al. found elevated insulin levels in CFS patients and Hotamisligil showed in mice that TNF-alpha (elevated in a large group of CFS patients cited above) induces insulin resistance (313, 314). Luo et al. report individual and interactive effects producing insulin resistance and hyperinsulinemia when the ventromedial hypothalamus of hamsters is infused with nor-epinephrine (NE) and serotonin (5-HT)(315). Both NE and 5-HT play roles in CFS. The importance of NE in stress, the HPA, neurally mediated hypotension and adrenal function is apparent as previously discussed. Serotonin is a potent stimulator of the CRH neurons in the lateral paraventricular nuclei (PVN) as well as the locus ceruleus-norepinephrine autonomic system (274). Demitrack stated that decreased serotonin activation of the HPA in CFS patients is an essential neuroendocrine feature of CFS and this observation is supported by others (316, 317). In work differentiating CFS from depressed patients, Cleare et al. suggest that CFS may be associated with increased 5-HT function and hypocortisolemia (318). These mediators which are important in CFS also contribute to insulin resistance.

A brief review of the physiologic roles of insulin is appropriate. Insulin causes glucose transport into cells. It activates anabolism by stimulating glucose utilization by both forming glycogen and breaking glucose down to precursors for fat and protein synthesis. It moves fats from circulation into storage, causing hydrolysis of circulating triglycerides to provide fatty acids for adipose uptake, then stimulates synthesis of triglycerides in adipose tissue and liver. It increases ribosomal protein synthesis. In addition, insulin inhibits catabolism. It blocks glycogenolysis and gluconeogenesis. It reduces lipolysis, the mobilization of free fatty acids and the oxidation of those fatty acids (319). It makes us ?fat?.

Other hormones contribute to the control of carbohydrate metabolism. In addition to insulin, the acute effect of growth hormone (GH) decreases blood glucose. This is opposed by the chronic effect of GH, ACTH and glucocorticoids, epinephrine (stress!) and glucagon and thyroxin. The net direction and activity of catabolism or anabolism is governed primarily by the relative concentrations of insulin and glucagon. Hypoglycemia is a brisk stimulus for production of glucocorticoids and growth hormone and this is useful for laboratory provocation testing (319).

Chronic fatigue syndrome patients have been observed to have abnormalities in these relationships. Decreased GH release in response to insulin-induced hypoglycemia has been reported in controlled studies of CFS patients by Allain et al. and Moorkins et al., though not observed in a smaller study by Cleare et al. (313, 320, 321). Conflicting data exist regarding the GH metabolite IGF-1, also called somatomedin C (52, 322). The larger series showed that somatomedin C in CFS patients was lower than in healthy controls (52).

Causes of insulin resistance are heterogeneous. Autoimmunity can play a role, directed against circulating insulin (common but usually insignificant) and receptors (rare). Cross-reactivity of insulin and IGF-1 exists with low affinity binding of little consequence (323). Decreased numbers of insulin receptors (down-regulation) are seen in obesity, following glucocorticoid therapy, oral contraceptive therapy, and in acromegaly (324). Hypercortisolism from chronic or maladaptive stress predictably might also decrease numbers of insulin receptors. Hypothyroidism causes reduced binding of insulin to rat liver membranes (325). Receptor down-regulation is caused by insulin secreting tumors and is a feature of both a severe form of ovarian dysfunction with virilization and acanthosis nigricans in young women and PCOS (318).

The insulin receptor in the cell membrane surface seems of less consequence than the glucose transporters which it stimulates like a garage door opener on the ceiling opens the door. There are five species or isoforms of these glucose transporters located in different tissues and having different properties. The most important of these is Glut-4, highly expressed only in skeletal muscle, adipose tissue and heart muscle. The isoforms Glut-1 (erythrocytes and other tissues) and Glut-3 (brain) have a high affinity for insulin and are thought less likely effected by insulin resistance. Glut-4, which accounts for most post-prandial glucose uptake (skeletal muscle absorbs 80 to 90% of all insulin-stimulated glucose uptake) has a much lower affinity for insulin and Glut-2 (liver and pancreatic B-cells) has the lowest affinity for insulin (324, 318). The skeletal muscle, liver and B-cells then may be most effected by insulin resistance. This may explain some of the clinical features of insulin-resistant non-diabetic patients. In summary, the exact mechanisms of insulin resistance are complex, multiple and remain incompletely defined.

Unfortunately, there is no real discussion of clinical symptoms in hyperinsulinemic insulin-resistant patients. The texts of endocrinology seem to discuss the phenomenon solely as a pre-diabetic condition (324). From the foregoing discussion of PCOS in which insulin resistance is the underlying cause of the disorder and through the preceding paragraphs it is evident that insulin resistance and hyperinsulinemia can cause symptoms.

My first contact with this was Pullen?s paper describing hyperinsulinemia mimicking Meniere?s disease and causing migraine headache, given at the 1985 World Congress of ORL (326). Clinical experience with our series of patients confirms that symptoms include and far exceed vertigo and headache. Prominent are CFS symptoms and hypoglycemic symptoms in which patients feel anxious, irritable and lightheaded (brain = Glut-3) while peripheral blood is hyperinsulinemic but euglycemic (muscle, liver and B-cells = Glut-4 and 2). Patients are usually physically obese but they may be very slender indeed and as has often been observed about CFS patients, these are the sickest ones.

Pullen advocated the four-hour oral glucose tolerance test (oGTT) with paired glucose and insulin assays to diagnose hyperinsulinemia and this is an excellent test (326). Once prohibitively expensive, it now costs only $200 at our county hospital laboratory. Normal data is provided by a 1987 study of 100 healthy volunteers who were ?pedigreed? normal with both a euglycemic insulin clamp test and standard oGTT, then given a 75 gm oGTT with blood aliquots divided for both glucose and insulin assay (327). These data are consistent with work cited by Olefsky (324). As a rule of thumb, serum insulin normally should not exceed 100mcU/mL after the 75gm oral challenge. Many patients demonstrate significant hypoglycemia when the high levels of insulin suddenly seem to break through the resistance: what I call the ?ketchup bottle effect?. A large series of patients will show a spectrum of responses grading to type II diabetes mellitus.

Treatment of symptomatic insulin resistance is simple: Nutritional supplementation, reduction of dietary carbohydrates (since they stimulate further hyperinsulinemia) and as needed, prescription drugs designed to increase insulin receptor sensitivity (metformin and rosiglitazone) (328). These steps are basically the same as the treatment for PCOS, which shares the same underlying pathology (307, 309). Patients? results are dramatic and improvement is sustainable.

Summary

Insulin resistance and hyperinsulinemia are importantly associated with CFS. Studies have shown elevated insulin levels in CFS patients. Insulin resistance may be induced by TNF-alpha, NE and 5-HT, all abnormal in CFS patients. Insulin is opposed by both glucocorticoids and epinephrine, both elevated by the chronic stress important in the histories of many CFS patients. Causes of insulin resistance are complex and multiple, with insulin receptor sites reduced in number after therapeutic doses of glucocorticoids and steroid sex hormones. The most vulnerable parts of the receptor apparatus are the glucose transporters with insulin affinity which varies by tissue-specific isoform. I suspect that the high insulin-affinity of brain receptors compared to the low affinity of pancreas and liver receptors explains hypoglycemic symptoms in insulin resistant patients with normal values of blood glucose. At the brain, insulin function is excessive relative to glucose levels. This creates symptoms.

A conceptually simple and relatively inexpensive test seems to be diagnostic for the little-recognized condition of symptomatic insulin resistance and hyperinsulinemia. Recently nearly replaced by the use of fasting glucose levels and hemoglobin A1c assays, the oGTT has found new utility in comparing glucose and insulin response. Treatment is also conceptually simple and gives results which are most gratifying both to patient and physician.


Thyroid hormone dysfunction

The role of the thyroid gland in CFS goes far beyond the comfortably oversimplified model of primary hypothyroidism that we learned during our training. In addition, simple measurements of thyroid stimulating hormone (TSH) and thyroxin (T4) are inadequate to evaluate thyroid hormone function in the patient with CFS. Fortunately, newer concepts about thyroid hormone function are now being discussed. Also, more thorough laboratory tests are available which will be sufficient for most clinical situations, if ordered and interpreted with understanding. To preface, a brief review of thyroid physiology will be useful.

The hypothalamus synthesizes thyrotropin-releasing hormone (TRH) which is conveyed through the hypophysial stalk to the anterior pituitary, where it stimulates production of thyrotropin (thyroid-stimulating hormone, TSH). In turn, TSH is the major regulator of the morphology of the thyroid gland and stimulates production and release of thyroid hormones. These hormones are made using the thyroid peroxidase (TPO) enzyme to bind iodine onto tyrosyl residues which are then coupled to form thyroid hormones and stored, bound on thyroglobulin (TG). The thyroid is the only endocrine gland which stores hormone – about 100 days? supply. Lysosomal proteases later cleave the bond to TG and release the thyroid hormone into circulation (329). At least three important forms of thyroid hormone exist and it is crucial to understand their properties. Thyroxin (3, 5, 3?, 5? tetra-iodothyronine, T4) is the most plentiful product of the thyroid gland, followed distantly by 3, 5, 3? tri-iodothyronine (T3) and then by a tiny amount o