Abstract: Several different meanings have been attached to the term "chemical sensitivity" by those who use it. Feeling ill from odors is a symptom reported by approximately one-third of the population. The syndrome of chemical sensitivity, frequently called "Multiple Chemical Sensitivity" or "MCS" has been the subject of three federally-sponsored workshops; at least five different case definitions for research on MCS have been proposed. In contrast, the hypothesis that chemical sensitivity may be a mechanism for disease posits that a broad spectrum of "recognized" chronic illnesses, ranging from asthma and migraine to depression and chronic fatigue, may be the consequence of environmental chemical exposures. According to this theory, a two-step process occurs: (1) an initial salient exposure event(s) (for example, a one-time, intermittent, or continuous exposure to pesticides, solvents, or air contaminants in a sick building) interacts with a susceptible individual, causing loss of tolerance for everyday, low level chemical inhalants (car exhaust, fragrances, cleaning agents), as well as for foods, drugs, alcohol, and caffeine; (2) thereafter, such common, formerly well-tolerated substances trigger symptoms, thus perpetuating illness. "Masking" (acclimatization, apposition, and addiction) may hide these exposure-symptom relationships, thus obfuscating the environmental etiology of the illness. Accumulating clinical observations lend credence to a view of chemical sensitivity as an emerging theory of disease causation and underscore the need for its testing in a rational, scientific manner. While chemical sensitivity may be the consequence of chemical exposure, the term "toxicant-induced loss of tolerance" more fully describes the two-step process under scrutiny.

Trial of a selective acetylcholinesterase inhibitor, galanthamine hydrobromide, in the treatment of chronic fatigue syndrome. Snorrason E, Geirsson A, Stefansson K. Journal of Chronic Fatigue Syndrome 1996; 2(2/3): 35-54.

Abstract: The purpose of the study was to search for a means of diminishing the plight of patients with chronic fatigue syndrome (CFS) and to test the hypothesis that central to the pathogenesis of CFS is a cholinergic defect. Forty-nine patients who fulfilled consensus criteria for CFS were treated with the acetylcholinesterase inhibitor, galanthamine hydrobromide. Thirtynine patients finsihed the study according to the protocol with 43% reporting 50% improvement whereas patients in the placebo group reported only 10% improvement in the same parameters of CFS. The improvement of patients on galanthamine was in most cases gradual and reached significance for the group only after four to eight weeks. The improvement was stable, and no patients who reported over 50% improvement on galanthamine relapsed to a pretrial level of any symptom. One of the most surprising effects was the dramatic improvement of sleep disturbances that occurred in most patients on this medication: more than 60% of the patients who finished the study reported over 70% improvement in sleep deficit. If the subjective report by patients can be proved by objective means, this would be the first demonstration of a drug that can be used to correct a sleep disturbance that also influences a specific stage in normal sleep. The most common adverse effect of galanthamine, as given in this study, was nausea that was dose-dependent and reversible. Galanthamine hydrobromide is relatively safe and appears to be an effective medication against many symptoms of CFS. But the positive results of this study have to be interpreted cautiously because of methodological limitations of this trial. First, this study was originally organized as a double-blind, placebo-controlled trial but was changed to an optional crossover after two weeks of treatment. Also, the adverse effects of the active drug in 30% of patients could compromise the double-blind. With these limitations in mind, it is nevertheless tempting to conclude that this study lends an indirect support to our hypothesis that a cholinergic deficit may play a role in the pathogenesis of the syndrome.

Effect of high doses of essential fatty acids on the postviral fatigue syndrome. Behan PO, Behan WMH, Horrobin D. Acta Neurologica Scandinavica 1990; 82: 209-216.

Abstract: Sixty-three adults with the diagnosis of the postviral fatigue syndrome were enrolled in a double-blind, placebo-controlled study of essential fatty acid therapy. The patients had been ill for from one to three years after an apparently viral infection, suffering from severe fatigue, myalgia and a variety of psychiatric symptoms. The preparation given contained linoleic, gamma-linolenic, eicosapentaenoic and docosahexaenoic acids and either it, or the placebo, was given as 8 x 500 mg capsules per day over a 3-month period. The trial was parallel in design and patients were evaluated at entry, one month and three months. In consultation with the patient the doctors assessed overall condition, fatigue, myalgia, dizziness, poor concentration and depression on a 3-point scale. The essential fatty acid composition of their red cell membrane phospholipids was analysed at the first and last visits. At 1 month, 74% of patients on active treatment and 23% of those on placebo assessed themselves as improved over the baseline, with the improvement being much greater in the former. At 3 months the corresponding figures were 85% and 17% (p less than 0.0001) since the placebo group had reverted towards the baseline state while those in the active group showed continued improvement. The essential fatty acid levels were abnormal at the baseline and corrected by active treatment. There were no adverse events. We conclude that essential fatty acids provide a rational, safe and effective treatment for patients with the post-viral fatigue syndrome.

The eight myths of Operation 'Desert Storm' and Gulf War syndrome. Medicine, Conflict and Survival Nicolson GL, Nicolson NL. 1997; 13(2): 140-46.

Abstract: Several conventional claims regarding Gulf War Syndrome are criticized: that Gulf War veterans are no sicker than the civilian population as a whole; that Gulf War Syndrome is a myth invented by the press; that GWS cannot be defined as a legitimate medical syndrome; that since its cause cannot be determined, it is not a problem associated with Operation 'Desert Storm'; that the US and UK governments are doing all they can to investigate and treat illness in veterans or deny existence of over 100,000 cases in veterans and their families; that GWS will settle without treatment; that the armed forces were well prepared for integrated conflict involving chemical and biological warfare in the Middle East, increasing the risk of this in the future.

Serum angiotensin-converting enzyme as a marker for the chronic fatigue-immune dysfunction syndrome: a comparison to serum angiotensin-converting enzyme in sarcoidosis. Lieberman J, Bell DS. American Journal of Medicine 1993; 95(4): 407-12.

Abstract: PURPOSE: To study the reliability of a serum angiotensin-converting enzyme (ACE) assay as a marker for the chronic fatigue-immune dysfunction syndrome (CFIDS), and to compare some enzyme characteristics of ACE in CFIDS with that in sarcoidosis. PATIENTS AND METHODS: Forty-nine patients with CFIDS and 56 endemic control subjects from Lyndonville, New York, and Charlotte, North Carolina; plus 23 untreated patients with active sarcoidosis, 24 with sarcoidosis receiving corticosteroid therapy, and 32 patient controls without sarcoidosis from California. Serum ACE levels were determined with a spectrophotometric method. The effect of freezing and thawing and the effect of storage at 4 degrees C were compared between CFIDS and sarcoidosis samples. RESULTS: Serum ACE levels were elevated in 80% of patients with CFIDS and 30% of endemic control subjects as compared with 9.4% of nonendemic California control subjects. The ACE activity in CFIDS differed from that in sarcoidosis because of its lability with storage at 4 degrees C in CFIDS and its partial activation with freezing and thawing. Thus, ACE activity was elevated in the majority of CFIDS patients either upon initial assay or upon a subsequent assay after refreezing. ACE activity was elevated in 87% of patients with active sarcoidosis and was not affected by storage or freezing and thawing. CONCLUSIONS: Serum ACE elevations may be a useful marker for CFIDS, especially if a method can be developed to distinguish ACE in CFIDS from that in sarcoidosis. The sensitivity for CFIDS was 80%, with 68% specificity in an endemic area. The increased prevalence of serum ACE elevations in endemic controls as compared with nonendemic controls suggests that an ACE increase may be an early manifestation of CFIDS and supports the concept that CFIDS is a definite disease state.

Chronic fatigue syndrome - influence of histamine, hormones and electrolytes. Dechene L. Medical Hypotheses 1993; 40(1): 55-60.

Abstract: The chronic fatigue syndrome is poorly understood. We believe the underlying causes in many atopics and women are a persistent infection and hypersensitivity to the immune-suppressive effects of histamine and certain pathogens. We believe much of the symptomatology can be explained by all four types of hypersensitivity (Gell and Coombs classification) in reaction to a pathogen, electrolyte disturbances which include sometimes permanent changes in cell membranes' ability to pass electrolytes, sometimes permanent biochemical changes in mitochondrial function, and disturbances of insulin and T3-thyroid hormone functions. We also explain in detail what 'fatigue' means for these patients. We present evidence from the medical literature for the plausibility of our hypotheses.

Effect of high doses of essential fatty acids on the postviral fatigue syndrome. Behan PO, Behan WMH, Horrobin D. Acta Neurologica Scandinavica 1990; 82: 209-216.

Abstract: Sixty-three adults with the diagnosis of the postviral fatigue syndrome were enrolled in a double-blind, placebo-controlled study of essential fatty acid therapy. The patients had been ill for from one to three years after an apparently viral infection, suffering from severe fatigue, myalgia and a variety of psychiatric symptoms. The preparation given contained linoleic, gamma-linolenic, eicosapentaenoic and docosahexaenoic acids and either it, or the placebo, was given as 8 x 500 mg capsules per day over a 3-month period. The trial was parallel in design and patients were evaluated at entry, one month and three months. In consultation with the patient the doctors assessed overall condition, fatigue, myalgia, dizziness, poor concentration and depression on a 3-point scale. The essential fatty acid composition of their red cell membrane phospholipids was analysed at the first and last visits. At 1 month, 74% of patients on active treatment and 23% of those on placebo assessed themselves as improved over the baseline, with the improvement being much greater in the former. At 3 months the corresponding figures were 85% and 17% (p less than 0.0001) since the placebo group had reverted towards the baseline state while those in the active group showed continued improvement. The essential fatty acid levels were abnormal at the baseline and corrected by active treatment. There were no adverse events. We conclude that essential fatty acids provide a rational, safe and effective treatment for patients with the post-viral fatigue syndrome.

A screening instument for chronic fatigue syndrome: reliability and validity. Jason LA, Ropacki MT, Santoro NB, et al. Journal of Chronic Fatigue Syndrome 1997; 3(1): 39-59.

Abstract: Because estimates of the prevalence of Chronic Fatigue Syndrome (CFS) have been quite variable, there is a need for a screening instrument and second stage medical assessment that will produce the most valid estimate of the CFS prevalence. In the present study, four groups of 15 subjects each were recruited: patients diagnosed with (1) CFS, (2) Lupus, (3) Multiple Sclerosis (MS), and (4) a healthy control group. Participants were interviewed twice over a two week period of time with a screening instrument comprising The Fatigue Scale and a newly configured section. The screening instrument had excellent test-retest and interrater reliability. This screening instrument therefore has utility for CFS community-based epidemiologic research. However, while the instrument differentiates patients with CFS from those who are healthy, it is less likely to distinguish CFS from other autoimmune diseases (especially Lupus). Thus, future community-based CFS prevalence studies whould encompass both a screening and a medical examination to adequately differentiate CFS from other illnesses with overlapping symptomatology. We recommend a two-stage research design with (1) a screening instrument with good sensitivity and (2) medical assessments of CFS positives from stage 1 to deal with the specificity problem.

An approach to studies of cancer subsequent to clusters of chronic fatigue syndrome: use of data from the Nevada State Cancer Registry. Levine PH, Atherton M, Fears T, Hoover R. Clinical Infectioius Diseases 1994; 18(Supp 1): S49-53.

Abstract: Chronic fatigue syndrome (CFS) has been increasingly associated with immune dysregulation, including depressed natural killer cell activity; this phenomenon is associated with increased susceptibility to cancer. Although anecdotal reports have suggested an association between CFS and cancer, particularly non-Hodgkin's lymphoma and brain cancer, there has been no a priori justification for evaluating such an association and no consideration of relevant parameters, such as length of latent period vs. tumor type. We reviewed data from the Nevada State Cancer Registry subsequent to a reported outbreak of a CFS-like illness in Nevada that occurred during 1984-1986. We concentrated on non-Hodgkin's lymphoma and brain/CNS tumors, with particular emphasis on persons 15-34 and 35-54 years of age. An upward trend in the incidence of brain/CNS tumors, which could be related to a national upward trend for this disease, was noted. No consistent trends were noted for non-Hodgkin's lymphoma. Because of the difficulties inherent in studies of cancer subsequent to various exposures, we evaluated the methodology for determining an association between outbreaks of CFS-like disease and cancer. We propose several approaches that should be considered in future studies for investigation of possible associations between CFS and cancer, including expected latent periods for specific tumors.

The economic impact of chronic fatigue syndrome. Lloyd A, Pender H. Medical Journal of Australia 1992; 157: 599-601.

Abstract: We studied the economic impact of chronic fatigue syndrome (CFS) on the individual, the government, and the community by calculating the direct and indirect costs related to this disorder in the Richmond Vally, a circumscribed semiurban population in northern New South Wales. Data were collected from cases identified in our previous prevalence study in this region; these cases provided the basis for the current data collection (1). Data regarding utilization of health care resources, income, and employment were obtained from patients by questionnaire. In addition, aggregate data from Medicare (the universal health care organization) on the incidence of and the fees charged for each schedule item for the patients in our survey were obtained. The conservative estimate of the per annum cost of CFS in the Richmond Valley, with a prevalence of 37.1 cases per 100,000 population, was $396,000. Direct medical costs of ~$2000 per patient per annum were recorded. If extrapolated to the entire population of Australia, we estimate that CFS would account for annual costs of at least $59 million. CFS accounts for a large but neglected area of health care resource utilization and imposes a significant economic burden. Reference: Lloyd AR, Hickie I, Boughton CR, Spencer O, Wakefield D. The prevalence of chronic fatigue syndrome in an Australian population.

Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors. Visser J, Lentjes E, Haspels I, Graffelman W, Blauw B, de Kloet R, Nagelkerken L. Division of Immunological and Infectious Diseases, TNO Prevention and Health, Leiden, The Netherlands.

BACKGROUND: In this study we tested the hypothesis that the increased sensitivity to glucocorticoids in chronic fatigue syndrome (CFS)-patients can be attributed to an altered functioning of their glucocorticoid receptors (GR). METHODS: For this purpose, affinity and distribution of the GR were studied in purified, peripheral blood mononuclear cells (PBMC) of 10 CFS patients and 14 controls along with the responsiveness of these cells to glucocorticoids in vitro. RESULTS: Affinity (Kd) and number of GR was not different in PBMC of CFS patients when compared with the controls (Kd, 12.9 +/- 8.9 nmol vs 18.8 +/- 16.2 nmol and GR number, 4,839 +/- 2,824/ cell vs 4,906 +/- 1,646/cell). Moreover, RT-PCR revealed no differences in GR messenger RNA expression. Nevertheless, PBMC from CFS patients showed an increased sensitivity to glucocorticoids in vitro. In CFS patients 0.01 micromol dexamethasone suppressed PBMC proliferation by 37%, whereas the controls were only suppressed by 17% (P < 0.01). Addition of phorbol 12-myristate 13-acetate to the cultures rendered the cells resistant to dexamethasone with regard to proliferation and IL-10 and IFN-gamma production, but not to IL-2 and TNF-alpha production in both patients and controls. No difference between patients and controls was observed in this respect CONCLUSIONS: In conclusion, PBMC of CFS patients display an increased sensitivity to glucocorticoids, which cannot be explained by number or affinity of the GR but should rather be attributed to molecular processes beyond the actual binding of the ligand to the GR.

Gastric emptying is slow in chronic fatigue syndrome Richard B Burnet and Barry E Chatterton Published 26 December 2004Article URL http://www.biomedcentral.com/1471-230X/4/32 © 2004 Burnet and Chatterton, licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract Gastrointestinal symptoms are common in patients with Chronic Fatigue Syndrome (CFS). The objective of this study was to determine the frequency of these symptoms and explore their relationship with objective (radionuclide) studies of upper GI function.Methods

Thirty-two (32) patients with CFS and 45 control subjects completed a questionnaire on upper GI symptoms, and the 32 patients underwent oesophageal clearance, and simultaneous liquid and solid gastric emptying studies using radionuclide techniques compared with historical controls.Results

The questionnaires showed a significant difference in gastric (p>0.01) symptoms and swallowing difficulty. Nocturnal diarrhoea was a significant symptom not previously reported. 5/32 CFS subjects showed slightly delayed oesophageal clearance, but overall there was no significant difference from the control subjects, nor correlation of oesophageal clearance with symptoms. 23/32 patients showed a delay in liquid gastric emptying, and 12/32 a delay in solid gastric emptying with the delay significantly correlated with the mean symptom score (for each p<<0.001).\

Conclusion GI symptoms in patients with chronic fatigue syndrome are associated with objective changes of upper GI motility

Low Urinary Serine Output is Associated with an Altered Faecal Microbial Flora in Chronic Fatigue[Syndrome]/Pain Patients Butt HL1,2, Dunstan RH2, McGregor NR2,3, Roberts TK2, Harrison TL2, and Grainger JR2 1 Collaborative Pain Research Unit (CPRU), Division of Microbiology & Infectious Disease, Hunter Area Pathology Service, John Hunter Hospital 2 Department of Biological Sciences, University of Newcastle, Newcastle 3 Faculty of Dentistry, University of Sydney, Westmead Hospital, Westmead Australia

Serine is an important precursor of tryptophan and serotonin. Previous studies of patients with chronic fatigue syndrome (CFS) demonstrated that serine (CFSUM2) was an important urinary metabolite discriminating between CFS from control subjects, and was negatively correlated with CFS neurological symptom index and total symptom index. Serine synthesis requires both alanine and glycine as precursors, and also as a result of microbial metabolism. The aim of this study is to determine if faecal microorganisms can produce serine, and how these organisms are quantitatively related to the total gastrointestinal microbial flora in CFS patients.

Three clinical faecal coliforms (Escherichia coli, Enterobacter cloacae and Proteus mirabilis) were incubated in defined broth and their metabolites were analyzed by a gas chromatogram (GC-MS). Serine was produced by the three organisms at varying concentrations. Other amino acids including serine precursors (alaine & glycine), leucine, phenylalanine and succinic acid, an organic acid, were also detected suggesting that the contribution of microbial metabolites by enteric organisms to achieve a balanced diet may be more important as previously thought.

Faecal samples from 27 CFS patients and four age and sex matched control subjects were studied. Quantitative bacteriology was performed on all samples. Seventeen (62.9%) CFS patients had a low % distribution of E.coli (<80% of total aerobic faecal count). In contrast none all four control subjects had a low % distribution of E.coli ( p < 0.03).

These studies showed that the low urinary excretion of serine in CFS patients reported in previous study was associated with a disturbed gastrointestinal microbial flora. Alteration in the aerobic microbial flora, particularly the Gram negative enteric organisms, may change the exogenous supply of serine and contribute to the increased symptoms expression of patients with CFS.

Eosinophil cationic protein serum levels and allergy in chronic fatigue syndrome. Conti F, Magrini L, Priori R, Valesini G, Bonini S. Allergy 1996: 51: 124-7.

Abstract: Chronic fatigue syndrome (CFS) is a syndrome of uncertain etiopathogenesis characterized by disabling fatigue associated with a variable number of somatic and/or neuropsychologic symptoms. In patients with CFS, several immunologic abnormalities can be detected, including a higher prevalance of allergy. The aim of this study was to determine whether CFS patients, well studied for their allergy profile, show signs of eosinophil activation, as detectable by the measurement in serum of eosinophil cationic protein (ECP) levels. In 35 consecutive CFS outpatients (diagnosis based on the Centers for Disease Control case definition), ECP was measured in serum by a competitive enzyme immunoassay (ECP-FEIA kit, Kabi Pharmacia Diagnostics, Uppsala, Sweden). Fourteen disease-free subjects with no history of CFS or allergy were selected as controls. ECP serum levels were significantly higher in CFS patients than in controls (18.0 ± 11.3 micrograms/l vs 7.3 ± 2.1 micrograms/l; P <0.01). In the CFS population, the prevalence of RAST positivity to one or more allergens was 77%, while no control showed positive RAST. Twelve of the 14 CFS patients with increased ECP serum levels were RAST-positive. However, CFS RAST-positive patients had no significantly higher ECP serum levels than CFS RAST-negative patients (19.3 ± 12.4 micrograms/l vs 13.6 ± 3.7 micrograms/l; P="0.4)." This is the first report of increased serum levels of ECP in CFS. On the basis of the available data, it is discussed whether eosinophil activation has a pathogenetic role in CFS or is linked to the frequently associated allergic condition, or, finally, whether a common immunologic background may exist for both atopy and CFS.