Pathogenesis Of Chronic Fatigue Syndrome Research Articles

A preliminary epidemiological study and discussion on traditional Chinese medicine pathogenesis of chronic fatigue syndrome in Hong Kong

Our purpose is to conduct an epidemiological study of chronic fatigue syndrome (CFS) and its syndrome types and symptoms of traditional Chinese medicine (TCM) among adults (20-50 years old) in Hong Kong, and to discuss the TCM pathogenesis. Cross-sectional questionnaire survey. Demographic data, CDC (1994) CFS diagnostic criteria, Trudie Chalder fatigue scale, and China national standard for TCM syndrome types criteria. Twenty to fifty years old adults by convenient sampling. One thousand and thirteen subjects were successfully interviewed. Five hundred and eighty-five subjects (57.8%) had different levels of fatigue. Sixty-five subjects (6.4%) met CFS diagnostic criteria. In terms of TCM syndrome types, blood stasis due to qi deficiency had the highest prevalence (35.7%) among CFS. In the 54 symptoms investigated in total, the first eight symptoms in order of appearing rates were soreness of loins and weakness in knees, poor spirit, lassitude, pain, insomnia, forgetting, vessels blood stasis, vertigo and dazzle. The mostly appeared tongue figures were pale and corpulent or pale dim tongue proper, white and white greasy tongue coating, and the mostly appeared pulse figure was sunken-thin. The point prevalence of CFS among adults of 20 to 50 years old was found to be 6.4%. The most prevalent TCM syndrome type was blood stasis due to qi deficiency. The TCM pathogenesis of CFS was deficiency of origin, mainly deficiency of qi and kidney, with excess of superficiality.

Cytokine production and modulation: Comparison of patients with chronic fatigue syndrome and normal controls

We studied cytokine production in 15 patients with chronic fatigue syndrome (CFS) and 23 controls. CFS patients' peripheral blood mononuclear cells were cultured with lipopolysaccharide or phytohemagglutinin. Enzymatic immunoassay indicated cytokine concentration in culture supernatants. CFS patients showed significantly lower mRNA levels and transforming growth factor-beta1 (TGF- β1) production. Cytokine dysregulation affects CFS pathogenesis. TGF- β1 may aid treatment because it affects CFS inflammatory characteristics.

Chronic Fatigue Syndrome and the Cholinergic Hypothesis

To the Editor: While the study by Dr Blacker and colleagues demonstrates that galantamine is not an effective treatment for persons with chronic fatigue syndrome (CFS), I do not believe that this negative outcome represents an appropriate test of the cholinergic hypothesis in the pathogenesis of CFS. Soreq and Seidman and Brenner et al have demonstrated in animal models of posttraumatic stress disorder and in Gulf War syndrome (a possible syndromic relative of CFS) that cholinergic neurons produce sustained and excessive amounts of AChE-R, an altered soluble variant of acetylcholinesterase. There is evidence that the sustained production of AChE-R derails the cholinergic neurons from performing their normal “signal-to-noise ratio” determination role in healthy brain function. If there is a cholinergic contribution to the pathogenesis of CFS, it would likely be the dysregulated production of AChE-R. The failure of galantamine to favorably influence the outcome of this syndrome could then be predicted because, being a cholinesterase inhibitor, it is likely inducing overproduction of AChE-R. An example of the importance of AChE-R for diseases with impaired cholinergic balance is myasthenia gravis: in an animal model the restoration of normal cholinergic function via the administration of EN101, an “antisense oligonucleotide” drug which lowers AChE-R in blood and muscle, was shown to be much more efficacious than anticholinesterases such as galantamine. Until a trial of CFS treatment with this agent is undertaken, I believe the cholinergic hypothesis deserves investigation as a plausible contributing explanation.

Differential-display PCR of peripheral blood for biomarker discovery in chronic fatigue syndrome

We used differential-display PCR of peripheral blood mononuclear cells (PBMCs) to search for candidate biomarkers for chronic fatigue syndrome (CFS). PBMCs were collected from a subject with CFS and an age- and sex-matched control before and 24 h after exercise. RNA expression profiles were generated using 46 primer combinations, and the similarity between the individuals was striking. Differentially expressed bands were excised, reamplified, and sequenced, yielding 95 nonredundant sequences, of which 50 matched to known gene transcripts, 38 matched to genes with unknown functions, and 7 had no similarity to any database entry. Most (86%) of the differences between the two subjects were present at baseline. Differential expression of ten genes was verified by real-time reverse-transcription PCR: five (cystatin F, MHC class II, platelet factor 4, fetal brain expressed sequence tag, and perforin) were downregulated, and the remaining five genes (cathepsin B, DNA polymerase epsilon4, novel EST PBMC191MSt, heparanase precursor, and ORF2/L1 element) were upregulated in the subject with CFS. Many of these genes have known functions in defense and immunity, thus supporting prior suggestions of immune dysregulation in the pathogenesis of CFS. Differential-display PCR is a powerful tool for identification of candidate biomarkers. Investigation of these markers in samples from well-designed epidemiological studies of CFS will be required to determine the validity of these candidate biomarkers. The real-time reverse-transcription PCR assays that we developed for assay of these biomarkers will facilitate high-throughput testing of these additional samples.

Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome

AbstractBecause the pathogenesis of Chronic Fatigue Syndrome (CFS) has yet to be determined, case definitions have relied on clinical observation in classifying signs and symptoms for diagnosis. The selection of diagnostic signs and symptoms has major implications for which individuals are diagnosed with CFS and how seriously the illness is viewed by health care providers, disability insurers and rehabilitation planners, and patients and their families and friends. Diagnostic criteria also have implications for whether research based on varying definitions can be synthesized. The current investigation examined differences between CFS as defined by Fukuda et al. (1994) and a set of criteria that has been proposed for a clinical Canadian Case definition. There were twenty-three participants who met the Canadian criteria, 12 in the CFS (Fukuda et al. (7) criteria) group and the 33 from the chronic fatigue (CF)-psychiatric group. Dependent measures included: work status, psychiatric comorbidity, symptoms, and...

Isoprenoid pathway dysfunction in chronic fatigue syndrome.

The isoprenoid pathway was assessed in 15 patients with chronic fatigue syndrome (CFS). The pathway was also assessed in individuals with differing hemispheric dominance to assess whether hemispheric dominance has any correlation with these disease states. The isoprenoid metabolites - digoxin, dolichol and ubiquinone - RBC membrane Na+-K+ ATPase activity, serum magnesium and tyrosine/tryptophan catabolic patterns were assessed. The free radical metabolism, glycoconjugate metabolism and RBC membrane composition were also assessed. Membrane Na+-K+ ATPase activity and serum magnesium levels were decreased while HMG-CoA reductase activity and serum digoxin levels were increased in CFS. There were increased levels of tryptophan catabolites - nicotine, strychnine, quinolinic acid and serotonin - and decreased levels of tyrosine catabolites -dopamine, norepinephrine and morphine - in CFS. There was an increase in dolichol levels, carbohydrate residues of glycoproteins, glycolipids, total/individual glycosaminoglycans (GAG) fractions and lysosomal enzymes in CFS. Reduced levels of ubiquinone, reduced glutathione and free radical scavenging enzymes as well as increased lipid peroxidation products and nitric oxide were noticed in CFS. The biochemical patterns in CFS correlated with those obtained in right hemispheric dominance. The role of hypothalamic digoxin and neurotransmitter-induced immune activation, altered glycoconjugate metabolism and resultant defective viral antigen presentation, NMDA excitotoxicity and cognitive and mitochondrial dysfunction in the pathogenesis of CFS is stressed. CFS occurs in individuals with right hemispheric dominance.

Diagnostic evaluation of 2', 5'-oligoadenylate synthetase activities and antibodies against Epstein-Barr virus and Coxiella burnetii in patients with chronic fatigue syndrome in Japan.

To investigate the association of viral infections with chronic fatigue syndrome (CFS), we assayed 2', 5'-oligoadenylate synthetase (2-5AS) activities in peripheral blood mononuclear cells from CFS patients in Japan. These patients were diagnosed in two hospitals, H1 and H2, located in different areas of the country. The activities were detected in 19 (86%) and 7 (32%) of each of the 22 patients in H1 and H2, respectively, while they were detected in only four (11%) out of the 38 healthy controls. IFN-alpha was similarly detected in a few CFS patients and healthy controls. We also assayed the antibody titers against Epstein-Barr virus (EBV) and Coxiella burnetii in these patients. The EBV anti-EA-IgG antibodies were detected in two (9%) and seven (32%) of each of the 22 patients in H1 and H2, respectively. Anti-C. burnetii IgG antibodies were detected in six (27%) out of 22 patients in H1 but not in 22 patients in H2, while they were detected in one (11%) of the nine healthy controls. Some CFS patients may be associated with EBV or C. burnetii infection. There were some statistical correlations between the 2-5AS activities and antibody titers of EA-IgG (P < 0.05, Student's t-test) but not to the antibody titers of C. burnetii. The up-regulation of 2-5AS activities suggests immunological dysfunctions with some virus infections in the CFS patients. Our results indicate that 2-5AS activities are useful for a diagnostic marker of CFS and for exploring the complicated pathogenesis of CFS.

Chronic fatigue syndrome: new evidence for a central fatigue disorder.

Considerable evidence points towards a prominent role for central nervous system (CNS) mechanisms in the pathogenesis of chronic fatigue syndrome (CFS), a disorder characterized chiefly by persistent, often debilitating, fatigue. We wished to characterize circulating profiles of putative amino acid modulators of CNS 5-hydroxytryptamine (5-HT; serotoninergic) and dopaminergic function in CFS patients at rest, as well as during symptom-limited exercise and subsequent recovery. Groups of 12 CFS patients and 11 age- and sex-matched sedentary controls, with similar physical activity histories, underwent ramp-incremental exercise to the limit of tolerance. Plasma amino acid concentrations, oxygen uptake and ratings of perceived exertion were measured at rest, and during exercise and recovery. Peak oxygen uptake was significantly lower in the CFS patients compared with controls. Rating of perceived exertion in the patients was higher at all time points measured, including at rest, relative to controls. Levels of free tryptophan (free Trp), the rate-limiting 5-HT precursor, were significantly higher in CFS patients at exhaustion and during recovery, whereas concentrations of branched-chain amino acids (BCAA) and large neutral amino acids (LNAA) were lower in CFS patients at exhaustion, and for LNAA also during recovery. Consequently, the [free Trp]/[BCAA] and [free Trp]/[LNAA] ratios were significantly higher in CFS patients, except at rest. On the other hand, levels of tyrosine, the rate-limiting dopaminergic precursor, were significantly lower at all time points in the CFS patients. The significant differences observed in a number of key putative CNS 5-HT and dopaminergic modulators, coupled with the exacerbated perception of effort, provide further evidence for a potentially significant role for CNS mechanisms in the pathogenesis of CFS.

Modification of the functional capacity of sarcoplasmic reticulum membranes in patients suffering from chronic fatigue syndrome

In chronic fatigue syndrome, several reported alterations may be related to specific oxidative modifications in muscle. Since sarcoplasmic reticulum membranes are the basic structures involved in excitation–contraction coupling and the thiol groups of Ca 2+ channels of SR terminal cisternae are specific targets for reactive oxygen species, it is possible that excitation–contraction coupling is involved in this pathology. We investigated the possibility that abnormalities in this compartment are involved in the pathogenesis of chronic fatigue syndrome and consequently responsible for characteristic fatigue. The data presented here support this hypothesis and indicate that the sarcolemmal conduction system and some aspects of Ca 2+ transport are negatively influenced in chronic fatigue syndrome. In fact, both deregulation of pump activities (Na +/K + and Ca 2+-ATPase) and alteration in the opening status of ryanodine channels may result from increased membrane fluidity involving sarcoplasmic reticulum membranes.

Normal production of inflammatory cytokines in chronic fatigue and fibromyalgia syndromes determined by intracellular cytokine staining in short-term cultured blood mononuclear cells.

It has been proposed that cytokines play a role in the pathogenesis of chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS). However, different studies have reported conflicting results using enzyme-linked immunosorbent assay or polymerase chain reaction to detect cytokines in these conditions. In the present study, for the first time, the production of inflammatory [interleukin (IL)-1alpha, IL-6, and TNF-alpha] and anti-inflammatory (IL-10) cytokines by CD14+ and CD14- peripheral blood mononuclear cells (PBMC) from chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS) patients and sex- and age-matched normal subjects was investigated at the level of individual cells using the technique of intracellular cytokine staining and flow cytometry. Cultures were carried out in the presence of polymyxin B to inhibit the effect of endotoxins on cytokine production by monocytes. The mean intensity of fluorescence (MIF) and percentage of CD14+ (monocytes) and CD14- (lymphocytes) cytokine-producing mononuclear cells were comparable in patients and controls in either unstimulated or IFN-gamma-stimulated conditions. Our study indicates that dysregulation of cytokine production by circulating monocytes or non-monocytic cells (lymphocytes) is not a dominant factor in the pathogenesis of CFS/FMS.

Variability in diagnostic criteria for chronic fatigue syndrome may result in substantial differences in patterns of symptoms and disability.

Chronic fatigue syndrome (CFS) is an illness that involves severe, prolonged exhaustion as well as neurologic, immunologic, and endocrine system pathology. Because the pathogenesis of CFS has yet to be determined, case definitions have relied on clinical observation in classifying signs and symptoms for diagnosis. The current investigation examined differences between CFS as defined by Fukuda and colleagues and a set of criteria that has been stipulated for myalgic encephalomyelitis (ME). Dependent measures included psychiatric comorbidity, symptom frequency, symptom severity, and functional impairment. The ME and Fukuda et al. (1994) CFS criteria were compared with a group having chronic fatigue due to psychiatric reasons. Significant differences occurred primarily with neurologic, neuropsychiatric, fatigue/weakness, and rheumatological symptoms. These findings suggest that it might be inappropriate to synthesize results from studies of this illness that use different definitions to select study populations.

Integration of gene expression, clinical, and epidemiologic data to characterize Chronic Fatigue Syndrome

BackgroundChronic fatigue syndrome (CFS) has no diagnostic clinical signs or diagnostic laboratory abnormalities and it is unclear if it represents a single illness. The CFS research case definition recommends stratifying subjects by co-morbid conditions, fatigue level and duration, or functional impairment. But to date, this analysis approach has not yielded any further insight into CFS pathogenesis. This study used the integration of peripheral blood gene expression results with epidemiologic and clinical data to determine whether CFS is a single or heterogeneous illness.ResultsCFS subjects were grouped by several clinical and epidemiological variables thought to be important in defining the illness. Statistical tests and cluster analysis were used to distinguish CFS subjects and identify differentially expressed genes. These genes were identified only when CFS subjects were grouped according to illness onset and the majority of genes were involved in pathways of purine and pyrimidine metabolism, glycolysis, oxidative phosphorylation, and glucose metabolism.ConclusionThese results provide a physiologic basis that suggests CFS is a heterogeneous illness. The differentially expressed genes imply fundamental metabolic perturbations that will be further investigated and illustrates the power of microarray technology for furthering our understanding CFS.

Chronic Fatigue Syndrome in Psychiatric Patients

Several investigators have suggested that environmental chemicals or “pollutants” play a significant role in the pathogenesis of chronic fatigue syndrome (CFS). This study compares the reported exposures to environmental chemicals and other potentially toxic environmental factors of psychiatric patients with CFS and two sets of controls from the same practice who did not meet the criteria for CFS. All comparisons found that CFS patients reported significantly more exposures to potentially toxic substances than any of the control groups. The extensive scientific literature on chemical intolerance and sensitization to generally non-toxic levels of potentially toxic substances, and its possible relevance to the investigation of CFS, is discussed.

Corticospinal inhibition appears normal in patients with chronic fatigue syndrome.

The pathogenesis of chronic fatigue syndrome (CFS) remains unknown. Thresholds and latencies of motor evoked potentials (MEPs) in response to transcranial magnetic stimulation (TMS) are normal but intracortical inhibition has not been investigated. Eleven patients with CFS were compared with 11 control subjects. Each patient completed a questionnaire using visual analogue indices of pain, fatigue, anxiety and depression. Subjects released a button to initiate simple (SRTs) and choice reaction time (CRTs) tasks; for each task, movement times were measured between release of the initiation button and depression of a second button 15 cm away. Subjects held a 10 % maximum voluntary contraction in the thenar muscles of their dominant hand while TMS was applied to the motor cortex; the duration and extent of inhibition of surface electromyographic (EMG) activity were assessed at stimulus strengths above and below the threshold for MEPs. Patients had significantly (P < 0.05) higher mean indices of fatigue than of pain, anxiety or depression. Mean (+/- S.E.M.) SRTs (but not CRTs) were longer in patients (309 +/- 45 ms) than in controls (218 +/- 9 ms). Movement times were longer in patients for both SRTs and CRTs. TMS thresholds, expressed as a percentage of the maximum stimulator output, were not significantly (P > 0.05) different in both groups for both MEPs (patients, 34 +/- 3%; controls, 36 +/- 3%) and inhibition of voluntary contraction (patients, 29 +/- 2%; controls, 34 +/- 4%). The duration and extent of inhibition did not differ significantly between groups at any stimulus strength. The pattern of change in duration and extent of inhibition with increasing stimulus intensity was no different in the two groups. The duration and extent of corticospinal inhibition in patients with CFS did not differ from controls, adding further evidence to the notion that the feeling of fatigue and the slowness of movement seen in CFS is not manifest in corticospinal output pathways.

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome.

The prevalence of chronic widespread pain in the general population in Israel was comparable with reports from the USA, UK, and Canada. Comorbidity with fibromyalgia (FM) resulted in somatic hyperalgesia in patients with irritable bowel syndrome. One sixth of the subjects with chronic widespread pain in the general population were also found to have a mental disorder. Mechanisms involved in referred pain, temporal summation, muscle hyperalgesia, and muscle pain at rest were attenuated by the N-methyl-D-aspartate (NMDA) antagonist, ketamine, in FM patients. Delayed corticotropin release, after interleukin-6 administration, in FM was shown to be consistent with a defect in hypothalamic corticotropin-releasing hormone neural function. The basal autonomic state of FM patients was characterized by increased sympathetic and decreased parasympathetic systems tones. The severity of functional impairment as assessed by the Medical Outcome Survey Short Form (SF-36) discriminated between patients with widespread pain alone and FM patients. Chronic fatigue syndrome (CFS) occurred in about 0.42% of a random community-based sample of 28,673 adults in Chicago, Illinois. A significant clinical overlap between CFS and FM was reported. Cytokine dysregulation was not found to be a singular or dominant factor in the pathogenesis of CFS. A favorable outcome of CFS in children was reported; two thirds recovered and resumed normal activities. No major therapeutic trials in FM and CFS were reported over the past year.

A Comparison of the 1988 and 1994 Diagnostic Criteria for Chronic Fatigue Syndrome

Chronic Fatigue Syndrome (CFS) is an illness that involves severe, prolonged fatigue as well as neurological, immunological, and endocrinological system pathology. Because the pathogenesis of CFS has yet to be determined, case definitions have relied on clinical observation in classifying signs and symptoms for diagnosis. In an attempt to address various criticisms and inconsistencies in diagnostic criteria, there have been several revisions of the CFS case definition. The current investigation examined the differences between 1988 and 1994 definitions as well as participants who had a psychiatric explanation for their fatigue. Dependent measures included psychiatric comorbidity, symptom frequency, and functional impairment. The 1988 criteria, compared to the 1994 criteria, appeared to select a group of participants with more symptomatology and functional impairment, but these groups did not significantly differ in psychiatric comorbidity. Implications of these findings are discussed.

Voluntary motor function in patients with chronic fatigue syndrome

Introduction: The pathogenesis of chronic fatigue syndrome (CFS) remains unknown. In particular, little is known of the involvement of the motor cortex and corticospinal system. Methods: Transcranial magnetic stimulation (TMS) was used to assess corticospinal function in terms of latency and threshold of motor-evoked potentials (MEPs) in thenar muscles. Reaction times and speed of movement were assessed using button presses in response to auditory tones. Results: Patients had higher ( P<.05) self-assessed indices of fatigue (7/10) than for pain (5/10), anxiety (4/10) or depression (3/10). Mean (±S.E.M.) simple reaction times (SRTs) were longer ( P<.05) in the patients (275±19 ms) than in the controls (219±9 ms); choice reaction times (CRTs) were not significantly longer in the patients. Movement times, once a reaction task had been initiated, were longer ( P<.05) in the patients in both SRTs (patients, 248±13 ms; controls, 174±9 ms) and CRTs (patients, 269±13 ms; controls, 206±12 ms). There was no difference ( P>.05) in threshold or latency of MEPs in hand muscles between the patients (threshold, 54.5±2.2% maximum stimulator output [% MSO]; latency 22±0.3 ms) and controls (threshold 54.6±3.6% MSO; latency 22.9±0.5 ms). Regression analysis showed no correlation ( P>.05) of SRTs with either threshold for MEPs or fatigue index. Conclusion: Corticospinal conduction times and excitability were within the normal range despite a slower performance time for motor tasks and an increased feeling of fatigue. This suggests that the feeling of fatigue and the slowness of movement seen in CFS are manifest outside the corticospinal system.

Results of Isoproterenol Tilt Table Testing in Monozygotic Twins Discordant for Chronic Fatigue Syndrome

The pathogenesis of chronic fatigue syndrome (CFS) is unknown. Neurally mediated hypotension (NMH) has been suggested as a common comorbid condition or a potential underlying cause. We conducted a cotwin control study of 21 monozygotic twins who were discordant for CFS. One twin met the 1994 Centers for Disease Control and Prevention criteria for CFS, and the other twin was healthy and denied chronic fatigue. The twins were selected from a volunteer twin registry in which at least 1 member reported persistent fatigue. As part of a 7-day clinical evaluation, all 21 twin pairs were evaluated with a 3-stage tilt table test with isoproterenol hydrochloride for the assessment of NMH. The presence of NMH was defined as syncope or presyncope associated with a decrease of 25 mm Hg in blood pressure and no associated increase in heart rate. A positive tilt table test result was observed in 4 twins with CFS (19%) and in 4 healthy twins (19%). This difference was not statistically significant (matched pair odds ratio, 1.0; 95% confidence interval, 0.2-5.4; P>.90). Compared with the healthy twins, the twins with CFS reported more severe symptoms of CFS and NMH both in the week before and during the tilt table test. These results do not support a major role for NMH in CFS. They highlight the importance of selecting well-matched control subjects, as well as the unique value of the monozygotic cotwin control design in the study of this illness. Arch Intern Med. 2000;160:3461-3468.

Chronic fatigue syndrome: is it physical?

It is increasingly recognized that chronic fatigue syndrome (CFS) is heterogeneous. A significant proportion of patients fulfilling operative criteria for a diagnosis of CFS will also fulfill criteria for a psychiatric disorder, such as depression or somatization. Failure to recognize this heterogeneity prejudices attempts to understand CFS in cross-sectional studies. Fulcher and White recently reported a study of muscle strength, aerobic exercise capacity, and functional incapacity in a group of patients with CFS without concurrent psychiatric disorder, compared with patients with major depression and a group of normal but sedentary subjects.1 In an incremental treadmill exercise test, patients with CFS and patients with depression had lower peak oxygen consumption rates, maximal heart rates, and plasma lactate concentrations than the sedentary controls; but this reflected the shorter duration of exercise tolerated by these patients. At submaximal work rates, patients with CFS and depressed patients experienced greater perception of effort than sedentary controls at the same level of work. This is in keeping with the finding that such patients show greater sensitivity to bodily sensations than normal subjects. Overall, there was little difference between the patients with CFS and the depressed patients in exercise characteristics, yet the patients with CFS reported significantly greater physical fatigue and physical incapacity. The authors did find one important difference, however. Their patients with CFS were significantly weaker than either the depressed patients or the sedentary controls, as judged by measurement of quadriceps strength. This is the first study to demonstrate such physical weakness in patients with CFS, and the authors suggest that this is because the patients they studied were more coherent than those studied previously. Fatigue is a complex symptom. In its strictest sense, the word means “inability to sustain force,” indicating dysfunction in the neuraxis or neuromuscular apparatus, whether physiologic (after strenuous exercise) or due to disease processes. In its colloquial context (fatigare—to tire), it is the sensation experienced when the effort to perform work, whether physical, mental, or both, seems disproportionate for the task involved. Physiologic fatigue recovers with rest. Chronic fatigue typically does not. Although chronic fatigue is a common complication of a wide range of medical and neurologic diseases, such as multiple sclerosis and Parkinson's disease, it can also occur in the absence of readily definable disease, notably in CFS. What is the cause of this physical weakness in CFS? Fulcher and White think that it is related to physical deconditioning due to inactivity, and this view is supported by improvement in well-being, strength, and exercise capacity after a graded aerobic exercise program.2 However, graded exercise therapy improves tolerance and exercise capacity in many disorders, including muscle diseases such as mitochondrial myopathies.3 Some patients with CFS show abnormal increases in plasma lactate levels after exercise at low work rates.4 Heart rate responses to exercise in the 1995 study did not suggest that these patients with CFS were more “deconditioned” than those with normal lactate responses. They also proved less likely to have psychiatric disorder. Furthermore, recent spectroscopic studies of the forearm muscles, which are not usually subject to the effects of deconditioning, showed abnormal muscle energy metabolism in such cases.5 Deconditioning may well be an important factor in the pathogenesis of CFS, but these findings raise the possibility that some patients with CFS have a form of metabolic myopathy. Whatever the mechanisms underlying “fatigue,” exercise therapy is likely to become an increasingly important therapeutic modality in various fields and particularly in the management of chronic fatigue syndromes.

Investigation of Erythrocyte Oxidative Damage in Rheumatoid Arthritis and Chronic Fatigue Syndrome

A role of free radical scavenging for erythrocytes has previously been demonstrated, which is additional to their established role of gas exchange. In carrying out this role, erythrocytes become damaged by oxidation, which consumes endogenous reducing substances. It was therefore proposed that there exists a link between erythrocyte metabolism (particularly redox metabolism) and erythro-cyte shape and that both of these should be related to erythrocyte deformability. To look for evidence of oxidative damage in vivo, the erythrocytes were assessed for reduced glutathione (GSH), malondial-dehyde (MDA), methaemoglobin (metHb) and 2,3-diphosphoglyceric acid (2,3-DPG) in patients suffering from rheumatoid arthritis (RA), chronic fatigue syndrome (CFS) and healthy control subjects. Full blood counts, serum vitamin B12, erythrocyte folate, serum ferritin, serum iron, serum iron binding capacity and erythrocyte magnesium were also performed on all samples. Patients with RA had increased 2,3-DPG, GSH and metHb when compared with the control group as well as the expected decreased haemoglobin, haematocrit, and serum iron. There was evidence of oxidative damage in CFS with 2,3-DPG metHb and MDA increased in this group. An increase in GSH could also be demonstrated in a sub-group of the CFS patients. This damage may explain the shape changes (presumably accompanied by increased rigidity) that have been reported in erythrocytes in patients suffering from CFS and suggests a role for free radicals in the pathogenesis of CFS.