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Nicolson, GL., Gan, R and Haier, J. Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS, 2003, 111, 5, 557-566.
Previously we and others found that a majority of CFS patients showed evidence of systemic mycoplasmal infections, and their blood tested positive using a polymerase chain reaction (PCR) assay for at least one of the four following Mycoplasma species: M. fermentans, M. hominis, M. pneumoniae or M. penetrans.
Consistent with previous results, patients in the current study (n=200, CDC criteria '94) showed a high prevalence (overall 52%) of mycoplasmal infections. Using forensic PCR we also examined whether these same patients showed evidence of infections with Chlamydia pneumoniae (overall 7.5% positive) and/or active human herpes virus-6 (HHV-6, overall 30.5% positive).
Since the presence of one or more infections may predispose patients to other infections, we examined the prevalence of C. pneumoniae and HHV-6 active infections in mycoplasma-positive and -negative patients. Unexpectedly, we found that the incidence of C. pneumoniae or HHV-6 was similar in Mycoplasma-positive and -negative patients, and the converse was also found in active HHV-6-positive and -negative patients.
Control subjects (n=100) had low rates of mycoplasmal (6%), active HHV-6 (9%) or chlamydial (1%) infections, and there were no co-infections in control subjects. Differences in bacterial and/or viral infections in CFS patients compared to control subjects were significant.
Severity and incidence of patients' signs and symptoms were compared within the above groups. Although there was a tendency for patients with multiple infections to have more severe signs and symptoms (p<0.01), the only significant differences found were in the incidence and severity of certain signs and symptoms in patients with multiple co-infections of any type compared to the other groups (p<0.01).
There was no correlation between the type of co-infection and severity of signs and symptoms. The results indicate that a large subset of CFS patients show evidence of bacterial and/or viral infection(s), and these infections may contribute to the severity of signs and symptoms found in these patients.
[Ed. note: There is no information about symptoms such as post-exertional fatigue.]
Endresen, GK. Mycoplasma blood infection in chronic fatigue and fibromyalgia syndromes. Rheumatology International, 2003 Jul 16 [Epub ahead of print].
CFS and fibromyalgia syndrome (FMS) are characterised by a lack of consistent laboratory and clinical abnormalities. Although they are distinguishable as separate syndromes based on established criteria, a great number of patients are diagnosed with both.
In studies using PCR methods, mycoplasma blood infection has been detected in about 50% of patients with CFS and/or FMS, including patients with Gulf War illnesses and symptoms that overlap with one or both syndromes. Such infection is detected in only about 10% of healthy individuals, significantly less than in patients.
Most patients with CFS/FMS who have mycoplasma infection appear to recover and reach their pre-illness state after long-term antibiotic therapy with doxycycline, and the infection can not be detected after recovery. By means of causation and therapy, mycoplasma blood infection may permit a further subclassification of CFS and FMS. It is not clear whether mycoplasmas are associated with CFS/FMS as causal agents, cofactors, or opportunistic infections in patients with immune disturbances. Whether mycoplasma infection can be detected in about 50% of all patient populations with CFS and/or FMS is yet to be determined.
Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, and Jones JF. Complement activation in a model of chronic fatigue syndrome. Journal of Allergy and Clinical Immunology, 2003, 112, 2, 397-403.
The purpose of this study was to use an exercise and/or allergen challenge to induce the symptoms of CFS and to identify a biological marker that correlates with these symptoms.
Patients with CFS (n=32, CDC criteria '94) and age plus activity-matched, normal control patients (n=29) exercised for 20 minutes on a stationary bike at 70% of their predicted max work load. Patients from each group with positive skin test results were also challenged with intra-nasally administered relevant allergens. Symptoms were recorded for 2 weeks before and 1 week after each challenge, using 3 different instruments including symptom diaries.
Blood samples were taken before, and 0, 1, 6, and 24 hours after challenges. Levels of complement split products, cell-associated cytokines, and eosinophilic cationic protein (ECP) were measured. (In one report, ECP - a serum protein also elevated in allergic states - was increased in both allergic and nonallergic patients with CFS.) Mean preexercise and postexercise symptom scores were evaluated for each group.
Exercise challenge induced significant increases of the complement split product C4a, but not C3a or C5a, at 6 hours after exercise only in the CFS group (p<.01), regardless of allergy status. Mean symptom scores were significantly increased after exercise based on the use of a daily diary (p<.03) and a weekly diary (p<.01) for the CFS group only. Mean scores for the Multi-dimensional Fatigue Inventory categories "reduced activity" and "mental fatigue" were significantly increased in the CFS group only (p<.04 and p<.02, respectively).
From the discussion: "The exacerbation of symptoms after exercise is seen only in the CFS population. Exercise does not appear to exacerbate symptoms in other disease states associated with fatigue such as depression or autoimmune diseases including rheumatoid arthritis, systemic lupus erthymatosus, and multiple sclerosis. In fact, depressed persons usually report a relief of symptoms after exercise. Patients with rheumatoid arthritis tolerate moderate exercise as part of treatment without an exacerbation of clinical markers, immune markers, pain, or disease activity. Additionally, exercise intervention in patients with lupus and MS does not significantly increase fatigue and in some cases reduces fatigue.
Exercise challenges triggered the activation of the classic pathway of the complement system generating C4a only in patients with CFS. In healthy, trained subjects, intense exercise such as a 30-minute run, a 2.5-hour run, and a graded maximal exercise test on a bicycle ergometer led to increased C4a levels, with those levels returning to baseline values between 30 minutes and 3 hours after exercise. In our study, all subjects were untrained, and the intensity of the exercise bout was much less than what has been previously studied. These factors probably explain why our control patients did not show an elevation of C4a after the exercise challenge; these same factors make the elevation of C4a in patients with CFS even more unique...
Even though patients with CFS were symptomatic during the 2 weeks before each challenge, their symptoms were significantly increased only after the exercise challenge. Symptoms scores at 24 hours after exercise were significantly correlated with the increase of C4a levels at 6 hours after exercise.
Correlation of an increase in symptoms after exercise with biological markers may be a key factor in devising diagnostic tests for CFS and other fatiguing illnesses." Establishment of a role for complement activation products as markers or participants in production of illness require further study.
Davey, NJ., Puri, BK., Catley, M., Main, J., Nowicky, AV and Zaman, R. Deficit in motor performance correlates with changed corticospinal excitability in patients with chronic fatigue syndrome. International Journal of Clinical Practice, 2003, 57, 4, 262-264.
CFS is characterised by fatigue and musculoskeletal pain, the severity of which is variable. Simple reaction times (SRTs) and movement times (SMTs) are slowed in CFS. Our objective is to correlate the day-to-day changes in symptomatology with any change in SRT, SMT or corticospinal excitability.
Ten patients with CFS (CDC criteria '94) were tested on two occasions up to two years apart. Motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) of the motor cortex were recorded from the thenar muscles. Threshold TMS strength to evoke MEPs was measured to index corticospinal excitability. SRTs and SMTs were measured. The percentage change in both SRTs and SMTs between the two test sessions correlated with the percentage change in corticospinal excitability assessed according to threshold TMS intensity required to produce MEPs.
This study provides evidence that changing motor deficits in CFS have a neurophysiological basis. The slowness of SRTs supports the notion of a deficit in motor preparatory areas of the brain.
Siessmeier, T., Nix, WA., Hardt, J., Schreckenberger, M., Egle, UT and Bartenstein P. Observer independent analysis of cerebral glucose metabolism in patients with chronic fatigue syndrome. Journal of Neurology, Neurosurgery and Psychiatry, 2003, 74, 7, 922-928.
The aim of this study was to evaluate cerebral glucose metabolism, assessed by 18-fluorodeoxyglucose positron emission tomography (FDG-PET), in patients with CFS, using an observer independent analytical approach; and to characterise any observed alterations by correlating them with neuropsychological deficits.
26 patients (13 female, 13 male) with CFS (CDC criteria '92) were examined (cases of major depression were excluded). Their ages ranged from 26 to 61 years (mean 43 years). They underwent extensive psychometric testing including the hospital anxiety and depression scale (HADS) and the short form 36 item health questionnaire (SF-36). Brain FDG-PET was done in all the subjects. After stereotactic normalisation, single subject comparisons with an age and sex matched normal database (n=18) and a group comparison between the patients and normal controls were undertaken, along with additional correlation analyses between brain metabolism and psychometric test scores.
12 of the 26 patients showed no significant decrease in FDG uptake compared with the controls. Of the remaining 14, 12 showed hypometabolism bilaterally in the cingulate gyrus and the adjacent mesial cortical areas. Five of these 12 patients also had decreased metabolism in the orbitofrontal cortex. The two remaining patients had hypometabolism in the cuneus/praecuneus. Correlation analyses showed significant correlations between some test scores (anxiety, depression, health related quality of life) and regional reductions in glucose metabolism. There was no correlation between the latter and fatigue.
Although abnormalities in FDG-PET were only detectable in approximately half the CFS patients examined, and no specific pattern for CFS could be identified, PET may provide valuable information in helping to separate CFS patients into subpopulations with and without apparent alterations in the central nervous system.
"Our data therefore support the hypothesis that the CFS case definition does not define a single disease entity but rather recruits patients with different health problems but similar subjective complaints".
[Ed. note: The authors note that similar findings have been documented in patients with depression, especially in the dorsolateral prefrontal cortex and the anterior cingulate. However, they cannot determine if the hypometabolism is a triggering factor for CFS or the result of the illness. There was no evidence of abnormalities in the brain stem cf Costa et al 1995.]
Farquhar, WB., Hunt, BE., Taylor, JA., Darling, SE and Freeman, R. Blood volume and its relation to peak O2 consumption and physical activity in patients with chronic fatigue. American Journal of Physiology - Heart and Circulatory Physiology, 2002, 282: H66-H71.
Individuals with CFS experience a number of somatic complaints including severe, disabling fatigue, and exercise intolerance. We hypothesized that hypovolemia, through its interaction with central hemodynamics, would contribute to the exercise intolerance associated with this disorder. We examined blood volume, peak aerobic power, habitual physical activity, fatigue level, and their inter-relations to understand the physiological basis of this disorder. Seventeen patients who met the CDC criteria '94 and 17 age-matched controls participated in the study. Blood volume was assessed using a single bolus injection of Evans blue dye. Peak oxygen consumption was measured during exercise on an upright cycle ergometer. Supine cardiac output and stroke volumes were measured using CO2 re-breathing. Questionnaires were used to assess habitual physical activity and fatigue.
Patients displayed a trend for a 9% lower blood volume (p=0.084) and had a 35% lower peak oxygen consumption (p<.001). These two variables were highly related within the patients (r=.835, p=0.001) and the controls (r=.850, p=0.001). Peak ventilation and habitual physical activity were significantly lower in the patients. Fatigue level was not related to any of the measured physiological parameters within the CFS group.
Thus, individuals with CFS have a significantly lower peak oxygen consumption and an insignificant trend toward lower blood volume compared with controls. These variables were highly related in both subject groups, indicating that blood volume is a strong physiological correlate of peak oxygen consumption in patients with CFS.
[Ed. note: Chronic or acute hypovolemia could lower peak oxygen consumption (VO2) and cause exercise intolerance by reducing left ventricular stroke volume and cardiac output. Support for this concept comes from prior studies in healthy young and older adults where strong relationships among blood volume, maximal VO2, and physical activity were reported. Thus a potential vicious cycle exists with fatigue and the consequent decrease in physical activity leading to reductions in blood volume, stroke volume, and peak VO2. The initiating factors in this vicious cycle are unknown.]
Vanness, JM., Snell, CR., Strayer, DR., Dempsey L and Stevens, SR. Subclassifying chronic fatigue syndrome through exercise testing. Medicine & Science in Sports & Exercise, 2003, 35, 908-913.
Purpose: The purpose of this study was to examine physiological responses of persons with CFS to a graded exercise test.
Methods: Cardiopulmonary exercise tests were performed on 189 patients diagnosed with CFS (CDC criteria '88). Based on values for peak oxygen consumption, patients were assigned to one of four impairment categories (none, mild, moderate, and severe), using American Medical Association (AMA) guidelines. A one-way MANOVA was used to determine differences between impairment categories for the dependent variables of age, body mass index, percentage of predicted VO2, resting and peak heart rates, resting and peak systolic blood pressure, respiratory quotient (RQ), and rating of perceived exertion.
Results: Significant differences were found between each impairment level for percentage of predicted VO2 and peak heart rate. Peak systolic blood pressure values for the "moderate," and "severe" groups differed significantly from each other and both other groups. The more impaired groups had lower values. The no impairment group had a significantly higher peak RQ than each of the other impairment levels (all p<0.001). Peak VO2 values were less than predicted for all groups. Compared with the males, the women achieved actual values for peak VO2 that were closer to their predicted values.
It is apparent from this study that given the current CDC diagnostic criteria, any group of CFS patients may respond differently to exercise testing. This lack of uniformity in patient samples has been a major impediment to the development of a treatment for CFS. Stratifying CFS patients by disability category is one way of avoiding the problems associated with the broad ranging and subjective nature of the current CFS diagnostic criteria. The results from exercise testing can be used to differentiate between groups of patients all of whom present symptoms consistent with CFS... Stratifying patients based upon the AMA guidelines for functional impairment revealed unique cardiovascular profiles for the more impaired patients with respect to heart rate and blood pressure responses during exercise. With no history of heart failure or cardiac myopathy among these patients, their responses are consistent with cardiac autonomic dysfunction. However, it may not be possible to completely rule out other cardiac pathology without exhaustive testing. Alternative explanations for their reduced exercise capacities may range from psychological abnormalities, to neuroendocrinological or metabolic dysfunction, to postviral immune system activation. Although exploration of such issues is beyond the scope of this article, it is clear that variability among CFS patients is an important research issue in addition to consideration of differences between CFS patients and healthy controls. It is also apparent that ... many CFS patients are subject to significant impairment as a result of this condition.
Conclusion: Despite a common diagnosis, the functional capacity of CFS patients varies greatly. Stratifying patients by function allows for a more meaningful interpretation of the responses to exercise and may enable differential diagnosis between subsets of CFS patients.
[Ed. Note: Approximately half the subjects met the AMA guidelines for moderate to severe functional impairment. The lack of functional impairment in some patients is of concern, given the CDC definition of fatigue and its severity.]
Smirnova, IV and Pall, ML. Elevated levels of protein carbonyls in sera of chronic fatigue syndrome patients. Molecular Cell Biochemistry, 2003, 248, (1-2), 93-95.
Protein carbonyl levels, a measure of protein oxidation, were found to be significantly elevated (p<0.0005) in the sera of CFS patients vs. controls. In contrast, the total protein levels in sera of CFS patients were unchanged from those of controls. The elevated protein carbonyl levels confirm earlier reports suggesting that oxidative stress is associated with CFS and are consistent with a prediction of the elevated nitric oxide/peroxynitrite theory of CFS and related conditions.
Asbring, P and Narvanen, AL. Ideal versus reality: physicians perspectives on patients with chronic fatigue syndrome (CFS) and fibromyalgia. Social Science & Medicine, 2003, 57, 4, 711-720.
Encountering patients with CFS or fibromyalgia can cause dilemmas for physicians due to the uncertainty inherent in these illnesses. The aim of this study was to investigate: (1) How physicians in a Swedish sample describe and categorise patients with CFS and fibromyalgia; (2) What the character of CFS and fibromyalgia, with regard to diagnosing, treatment and medical knowledge/aetiology, mean to the physicians in encounters with patients; and (3) Which strategies physicians describe that they use in the encounter with these patients.
Semi-structured interviews were carried out with 26 physicians, specialists in various fields who all had some experience of either CFS or fibromyalgia. The results suggest that there is a discrepancy between the ideal role of the physician and reality in the everyday work in interaction with these patients. This may lead to the professional role being questioned.
Different strategies are developed to handle the encounters with these patients. The results also illuminate the physician's interpretations of patients in moralising terms. Conditions given the status of illness were regarded, for example, as less serious by the physicians than those with disease status. Scepticism was expressed regarding especially CFS, but also fibromyalgia. Moreover, it is shown how the patients are characterised by the physicians as ambitious, active, illness focused, demanding and medicalising. The patient groups in question do not always gain full access to the sick-role, in part as a consequence of the conditions not being defined as diseases.
Fisher, L and Chalder, T. Childhood experiences of illness and parenting in adults with chronic fatigue syndrome. Journal of Psychosomatic Research, 2003, 54, 439-443.
Objective: There are many similarities between CFS, the somatoform disorders and problems otherwise known as "medically unexplained symptoms." There is some evidence to suggest that a combination of inadequate parenting and early illness experience may predispose the individual to develop medically unexplained symptoms in adult life. The aim of this investigation was to compare the contributions of childhood experiences of illness and parenting in adults with CFS with a fracture clinic control group.
Method: A retrospective case control design was used. Thirty patients with a diagnosis of CFS (not defined) and 30 patients attending a fracture clinic in an inner London teaching hospital completed questionnaires measuring parental care and protection and were interviewed about childhood experiences of illness.
Results: There were no differences in childhood experience of illness in the two groups. However, logistic regression revealed that maternal overprotection and depression were associated with the diagnosis of CFS.
Conclusion: The findings may represent risk factors for the development of CFS in adult life. It is possible that maternal overprotection in particular is related to the formation of belief systems about avoiding activity that operate to adversely influence behaviour in patients with CFS.
[Ed. note: Children with an acute injury, which can be readily treated and which in most cases has a positive outcome, may not be appropriate controls for patients experiencing a chronic and disabling illness involving the central nervous system, which has an uncertain outcome, and for which there is limited help on the NHS. Moreover, CFS is surrounded by misinformation and disbelief. In other words, the two groups do not just differ on one variable, i.e. the absence\presence of a medical explanation. In relation to the findings, the uncertainty related to illnesses like CFS and MS can lead to anxiety, which in turn could affect recall bias and thus distort results.
There is no information of illness-related variables and it may be argued that assessment of a limited number of psycho-social 'predictors' could be construed as overly reductionistic. Finally, it should be noted that there is still no evidence that avoidance of activity is associated with the perpetuation of CFS. As this journal has no correspondence section, readers cannot be made aware of these 'flaws'.]
Jason, LA., Fricano, G., and Klein, SM. Relevance of phase theory to chronic fatigue syndrome. Psychology and Education - an Interdisciplinary Journal, 2003, 40, 20-26.
This paper examines different stage-theories in an effort to better understand and predict patient and family reactions to chronic illnesses. The concept of phases can provide caregivers and psychologists with a better idea of how patients might be feeling, especially when dealing with difficult to understand illnesses such as CFS. Although stage theories provide significant heuristic contributions to many scientific disciplines, these models have also sustained considerable criticism. Such models need to be carefully validated in order to prevent erroneous conclusions from being made.
Moss-Morriss, R and Petrie, KJ. Experimental evidence for interpretative but not attention biases towards somatic information in patients with chronic fatigue syndrome. British Journal of Health Psychology, 2003, 8, 195-208.
These researchers studied 25 patients with CFS (CDC criteria '94) and 24 matched, healthy controls. Results suggest that the patients with CFS are more likely to interpret ambiguous words such as chemical, weak, exhaust, and growth in a somatic or illness-related manner (e.g. exhaust would lead to a word-association response of weak or collapse, not car or pipe.) However, there was no evidence of an attentional bias for illness-related information (Stroop test). This means seeing a somatic relevant word did not distract them from another task (naming the colour of the lettering). The authors conclude that this supports the use of CBT, to reduce "interpretative bias", as this may heighten their experience of physical symptoms and maintain "their negative illness schemas".
[Ed. note: The authors recognise that the results could be the result of having a chronic physical illness. It is surprising that a second control group comprising patients with a disabling somatic disease was not included in the design.]
Smith, S and Sullivan, K. Examining the influence of biological and psychological factors on cognitive performance in chronic fatigue syndrome: a randomized, double-blind, placebo-controlled, crossover study. International Journal of Behavioral Medicine, 2003, 10, 2, 162-173.
The pathophysiology of CFS remains unclear; however, both biological and psychological factors have been implicated in establishing or maintaining this condition. People with CFS report significant and disabling cognitive difficulties such as impaired concentration that in some cases are exacerbated by exposure to chemical triggers. The aim of this study was to determine if neuropsychological deficits in CFS are triggered by exposure to chemicals, or perceptions about the properties of these substances.
Participants were 36 people with a primary diagnosis of CFS, defined according to CDC criteria. A randomized, double-blind, placebo-controlled, crossover design was used, with objective assessment of neuropsychological function and participant rating of substance type, before and after exposure to placebo or chemical trigger.
The results showed decrements in neuropsychological tests scores on three out of four outcome measures when participants rated the substance they had been exposed to as "chemical." No change in performance was found based on actual substance type.
The findings suggest that cognitive attributions about exposure to substances in people with CFS may be associated with worse performance on neuropsychological tasks. Psychological interventions aimed at modifying substance-related cognitions may reduce some symptoms of CFS.
Tiersky, LA., Matheis, RJ., Deluca, J., Lange, G and Natelson, BH. Functional status, neuropsychological functioning, and mood in chronic fatigue syndrome (CFS). Relationship to psychiatric disorder. Journal of Nervous and Mental Disease, 2003, 191, 5, 324-331.
In the current investigation, the role of psychiatric status in reducing health-related quality of life in CFS (CDC criteria '94) was examined. Four subject groups were compared on measures of functional well-being, mood, and neuropsychological status: individuals with CFS and no history of psychiatric illness (n=60), individuals who had current symptoms of psychiatric illness that began after their CFS diagnosis (n=21), individuals who had current symptoms of psychiatric illness that began before their CFS diagnosis (n=26), and a healthy sedentary control group (n=41).
Overall, it was found that individuals with CFS suffer from profound physical impairment. Concurrent psychiatric illness did not adversely affect physical functional capacity (MOS). However, as expected, concurrent psychiatric illness was found to reduce emotional well-being. Moreover, individuals with a psychiatric illness that predated the onset of CFS suffered the greatest emotional distress and had higher anxiety, anger (POMS) and neuroticism scores than the patients with no psychiatric problems. Fatigue scores were similar for all patient groups.
Thus, an individual's psychiatric history should be considered when attempting to understand the factors maintaining disability in CFS.
[Ed. note: The similar fatigue scores conflicts with the CBT model which predicts increased disability with psychiatric disorders like depression. The authors suggest there may be a subgroup with a physical disability, possibly with a 'neurological basis'. The scores for physical functioning in the no-psychiatric disorders group was below that of the patients with psychiatric disorders, i.e. they were more severely affected and psychiatric illness did not double the illness burden. This is consistent with research on other disorders. However, all three groups had scores indicating significant impairment and the patients with preexisting psychiatric illness performed more poorly on some of the cognitive tests.]
Blockmans, D., Persoons, P., Van Houdenhove, B., Lejeunea, M and Bobbaers, H. Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study. The American Journal of Medicine, 2003, 114, 9, 736-741.
Purpose. CFS has been associated with decreased function of the hypothalamic-pituitary-adrenal axis. Although neurally mediated hypotension occurs more frequently in patients with CFS than in controls, attempts to alleviate symptoms by administration of hydrocortisone or fludrocortisone have not been successful. The aim of this study was to investigate the effect of combination therapy (5 mg/d of hydrocortisone and 50 g/d of 9-alfa-fludrocortisone) on fatigue and well-being in CFS.
Methods. We performed a 6-month, randomized, placebo-controlled, double-blind, crossover study in 100 patients with CFS (CDC criteria '94). Between-group differences (placebo minus treatment) were calculated on a 10-point visual analog scale.
Results. Eighty patients completed the 3 months of placebo and 3 months of active treatment in a double-blind fashion. There were no differences between treatment and placebo in patient-reported fatigue or well-being. There were also no between-group differences in fatigue measured with the Abbreviated Fatigue Questionnaire, the Short Form-36 Mental or Physical Factor scores, or the Hospital Anxiety and Depression Scale.
Conclusion. Low-dose combination therapy of hydrocortisone and fludrocortisone was not effective in patients with CFS.
[Ed. note: The mean cortisol levels were normal. The rationale for supplementation is therefore unclear. However, there was no between treatment differences when 20 patients with the lowest values were assessed as a subgroup.]
Darbishire, L., Ridsdale, L and Seed, PT. Distinguishing patients with chronic fatigue syndrome: a diagnostic study in UK primary care. British Journal of General Practice, 2003, 53, 441-445.
This study investigated patients presenting to 22 general practices in London and the South Thames region. Only 31% of the 141 patients presenting with a main symptom of fatigue lasting six months or more, were found to fulfil the criteria for CFS (CDC '94). Fatigue, distress and functioning, as well as associated symptoms were more severe in those with CFS. There were also other differences. About half in each group attributed their fatigue to mainly psychological causes.
The authors note the usefulness of differentiating between CFS and chronic fatigue.
[Ed. note: Diagnosis was made on the basis of self-report questionnaires and information from medical notes. Patients were not examined. These results challenge the view that differences between CF and CFS are of no medical interest.]
Evengard, B., Jonzon, E., Sandberg, A., Theorell, T and Lindh, G. Differences between patients with chronic fatigue syndrome and with chronic fatigue at an infectious disease clinic in Stockholm, Sweden. Psychiatry and Clinical Neurosciences, 2003, 57, 4, 361-368.
Background data were collected from patients presenting with fatigue at the clinic of infectious diseases at Huddinge University Hospital, Stockholm. The main purpose was to look for differences as to demographic and functional status for patients fulfilling 1994 criteria for CFS and chronic fatigue (CF). A cross-sectional questionnaire survey was performed using a variety of instruments. A thorough medical investigation was performed.
A total of 640 consecutive patients, 442 women (69%) and 198 men (31%), mean age 41 years (range: 10-65 years), were included in the present study. Two hundred and sixty-nine patients (42%) fulfilled the CFS criteria and 216 (34%) were diagnosed as having CF. For the total group of attending patients, the median duration of illness at diagnosis was 3.0 years (range: 0.5-50 years). Twenty-eight per cent reported exposure to stress at onset. Medical comorbidity was noted in 22% and psychiatric comorbidity in 13%. Past psychiatric history, defined as having been treated by a professional psychologist/psychiatrist, was reported in 12%. Fifty-four percent of all patients reported an acute onset of illness. More men with CFS had been on sick leave than men with CF.
No difference was found as to social situation, occupation and illness Attributions* for patients in the two categories. Patients with CFS reported in general a higher degree of 'sickness' with more self-reported somatic symptoms, more self-reported functional impairment and more absence from work. A higher degree of psychiatric comorbidity was observed in CF than in CFS patients. A majority of CFS patients (80%) had an acute infectious onset compared to 43% in the CF group.
Presently used criteria might, according to findings presented here, define two different patient categories in a population characterized by severe, prolonged fatigue. Because CFS patients (compared to patients with CF) have more somatic symptoms, more often report an infectious, sudden onset and have less psychiatric comorbidity, and CF patients seem to have more of an emotional, burn-out-like component one could speculate about the existence of different pathogenetic backgrounds behind the two diagnoses.
[Ed. Note: *re attributions: "More CFS patients (46% compared to 34% of CF patients) attributed the cause to infection. More patients with CF believed stress was a starter (24% compared to 16%) and more CF patients believed several factors were involved." The differences, however, did not reach statistical significance.
There were minimal differences in the level of fatigue (physical fatigue 18 for CFS versus 16 for CF). This may reflect the low ceiling of the measure used. It also supports the view that CFS is not a severe form of CF and the additional symptoms are a relevant source of disability, possibly more so than fatigue. This may be reflected in measures such as sick leave and self-reported functional impairment.]
Prins, JB., Elving, LD., Koning, H., Bleijenberg, G and van der Meer, JW. Diagnosing chronic fatigue syndrome: comparison of a protocol and computerised questionnaires. Netherlands Journal of Medicine, 2003, 61, 4, 120-126.
BACKGROUND: In the context of outpatient care and within the framework of scientific research, guidelines and measuring instruments have been developed to help improve CFS diagnostics. The purpose of this study was to measure the agreement between the evaluations of chronically fatigued patients by physicians using a CFS protocol and by researchers using computerised questionnaires.
METHODS: The sample consisted of 516 patients referred to an internal medicine outpatient clinic with complaints of chronic fatigue. Retrospectively the medical records and the computerised questionnaires were checked separately and compared to see whether the criteria for diagnosis of CFS had been met. In addition, the reasons for not diagnosing CFS were evaluated.
RESULTS: Agreement between the physicians' and the researchers' evaluations was 84%. Disagreement mostly concerned severity of fatigue and functional impairment, or premorbid exclusion criteria. A physical cause for the chronic fatigue was only found in 3% of the cases.
CONCLUSIONS: For physicians, questionnaire assessment may be complementary to the CFS protocol in optimising the process of diagnosing CFS.
Reyes, M., Nisenbaum, R., Hoaglin, DC., Unger, ER., Emmons, C., Randall, B., Stewart, JA., Abbey, S., Jones, JF., Gantz, N., Minden, S and Reeves, WC. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Archives of Internal Medicine, 2003, 163, 1530-1536.
We conducted a random digit-dialing survey and clinical examination to estimate the prevalence of CFS in the general population of Wichita, and a 1-year follow-up telephone interview and clinical examination to estimate the incidence of CFS. The survey included 33,997 households representing 90,316 residents. This report focuses on 7162 respondents aged 18 to 69 years. Fatigued (n=3528) and randomly selected nonfatigued (n=3634) respondents completed telephone questionnaires concerning fatigue, other symptoms, and medical history. The clinical examination included the Diagnostic Interview Schedule for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, laboratory testing, and a physical examination.
The overall weighted point prevalence of CFS, adjusted for non-response, was 235 per 100,000 persons (95% confidence interval, 142-327 per 100,000 persons). The prevalence of CFS was higher among women, 373 per 100,000 persons (95% confidence interval, 210-536 per 100 000 persons), than among men, 83 per 100,000 persons (95% confidence interval, 15-150 per 100,000 persons). Among subjects nonfatigued and fatigued for less than 6 months, the 1-year incidence of CFS was 180 per 100,000 persons (95% confidence interval, 0-466 per 100,000 persons).
CFS constitutes a major public health problem. Longitudinal follow-up of this cohort will be used to further evaluate the natural history of this illness.
Henningsen, P., Zimmerman, T and Sattel, H. Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review. Psychosomatic Medicine, 2003, 65, 528-533.
Meta-analytic integration confirms that the four functional somatic syndromes (IBS, nonulcer dyspepsia, FM, CFS) are related to (but not fully dependent on) depression and anxiety. In view of the relative independence from depression and anxiety, classification and treatment of these symptoms and syndromes as "common mental disorders" does not seem fully appropriate.
Hokama, Y., Uto, GA., Palafox, NA., Enlander, D., Jordan, E and Cocchetto, A. Chronic phase lipids in sera of chronic fatigue syndrome (CFS), chronic ciguatera fish poisoning (CCFP), hepatitis B, and cancer with antigenic epitope resembling ciguatoxin, as assessed with MAb-CTX. Journal of Clinical and Laboratory Analysis, 2003, 17, 4, 132-139.
Clinical reports and descriptions of CFS and chronic ciguatera fish poisoning (CCFP) show great similarities in clinical symptomology. These similarities in the literature suggested the exploration of lipids in sera of CFS, CCFP, and other diseases with the membrane immunobead assay (MIA), which is typically used for screening ciguateric ocean fish.
Sera from patients with other diseases, including hepatitis B, cancer, and diabetes, were included to assess the degree of specificity involved.
The undiluted acetone fraction of the 37 normal samples showed +/- activity to +activity with 16 no titer, 15 with 1:5 titer and two with 1:10 titer, and four with > or =1:40 titers. One hundred fifteen CFS sera showed 1 with 1+ and 114 with 2+ activity in the undiluted samples, 1 with 1:10 titer, 3 with 1:20 titer, 31 with 1:40 titer, 50 with 1:80 titer, and 30 with 160 titer. Thus 95.6% of the samples had > or =1:40 titer. Eight hepatitis B sera samples had > or =1:40 titers. Four CCFP samples had > or =1:40 titers. Three of 16 cancer samples had 1:40 titer. A significant increase (p<0.001) in the chronic phase lipids (CPLs) was shown relative to the normal group.
A preliminary chemical study in C18 octadecylsilyl columns showed all fractions (100% chloroform, 9:1 chloroform : methanol, 1:1 chloroform : methanol, and 100% methanol) to contain lipids reactive to MAb-CTX with different intensities. Prostaglandins were shown in 100% methanol fraction. Competitive MIA with crude fish ciguatoxin and CFS with synthetic JKLM ciguatoxin epitope suggested similarities in structure with ciguatoxin. This was compatible with the neuroblastoma assay demonstrated in the C(18) column fractions 9:1 and 1:1, chloroform: methanol solvents.
Huibers, MJ., Beurskens, AJ., Prins, JB., Kant, I., Bazelmans, E., Van Schayck, CP., Knottnerus, JA and Bleijenberg, G. Fatigue, burn-out, and chronic fatigue syndrome among employees on sick leave: do attributions make the difference? Occupational & Environmental Medicine, 2003, 60 (Suppl 1), I26-I31.
METHODS: This cross sectional study aimed to investigate relations between persistent fatigue, burnout, and CFS by describing the clinical features of a sample of 151 fatigued employees on sick leave. Using validated instruments, subgroups based on research criteria for CFS and burnout within the sample of fatigued employees and a reference group of 97 diagnosed CFS patients were compared. Analyses of covariance were performed.
RESULTS: A total of 66 (43.7%) fatigued employees met research criteria for CFS (except symptom criteria) and 76 (50.3%) met research criteria for burnout. "CFS-like employees" (fatigued employees who met CFS criteria) reported stronger somatic attributions than "non-CFS-like employees". Burnt out CFS-like employees were more depressed and distressed than CFS-like employees who were not burnt out. Burnout cases among the non-CFS-like employees had stronger psychological attributions than fatigued employees who were not burnt out. Compared to diagnosed CFS patients, CFS-like employees merely had a shorter duration of fatigue complaints. Burnt out CFS-like employees had stronger psychological attributions and were more distressed than CFS patients.
CONCLUSIONS: Fatigued employees shared many important characteristics with CFS patients, regardless of burnout status, and many fatigued employees met CFS criteria and/or burnout criteria. Differences however concerned the causal attributions that were made. This raises questions about the role of causal attributions: are they modified by fatigue complaints or do they determine illness outcome?
Kurup, RK and Kurup, PA. Hypothalamic digoxin, cerebral chemical dominance and myalgic encephalomyelitis. International Journal of Neuroscience, 2003, 113, 5, 683-701.
The isoprenoid pathway was assessed in 15 patients with CFS (Wessely 1991) and matched, healthy controls. The pathway was also assessed in individuals with differing hemispheric dominance to assess whether hemispheric dominance had any correlation with these disease states.
A number of abnormalities were found, including reduced levels of ubiquinone, reduced glutathione, and free-radical scavenging enzymes, as well as increased lipid peroxidation products and nitric oxide. The biochemical patterns correlated with those obtained in right hemispheric chemical dominance. "ME occurs in individuals with right hemispheric chemical dominance".
McCully KK, Smith S, Rajaei S, et al. Blood flow and muscle metabolism in chronic fatigue syndrome. Clinical Science, 2003, 104, 6, 641-647. Abstract, see ibid, no 55.
Naschitz JE, Rosner I, Rozenbaum M, et al. Successful treatment of chronic fatigue syndrome with midodrine: A pilot study. Clinical and Experimental Rheumatology, 2003, 21, 3, 416-417.
Peckerman, A., Chemitiganti, R., Zhao, CX, Dahl, K., Natelson, BH., Zuckier, L., Ghesani, N., Wang, S., Quigley, K and Ahmed, SS. Left ventricular function in chronic fatigue syndrome (CFS): data from nuclear ventriculography studies of responses to exercise and postural stress. FASEB JOURNAL, 2003, 17, 5, Pt. 2, A853-A853.
The main symptom of the CFS patient, i.e., chronic fatigue that is greatly exacerbated by even minor effort, is similar to that of a patient with left ventricular dysfunction. We hypothesized therefore that some patients with left ventricular dysfunction who do not show overt signs of cardiac insufficiency may nevertheless develop persistent, disabling fatigue and become diagnosed with CFS. To explore this possibility we performed nuclear ventriculography (MUGA) stress tests in 16 CFS patients and 4 controls.
The two groups had similar resting ejection fraction (EF) (67+/- 6 vs. 66 +/-9%). During maximal exercise, EF increased in controls but declined in CFS patients (mean change 8+/-8 vs. 6+/-12%, p<0.06). The decreases in EF tended to be greater in patients with more severe symptoms.
Using a decline in EF as a criterion, 13 CFS patients (81%) and 0 control subjects had positive tests (p<0.OO3). There were no group differences in levels of exertion, as indicated by similar cumulative work output, maximal heart rate, and increases in lactate levels (p>O.50). A similar pattern of changes in EF, i.e. increases in controls and declines in CFS patients, was observed in response to postural stress.
These preliminary data support the hypothesis that some cases of CFS may be explained and potentially treated as a problem with left ventricular function.
Renan MJ. Is hypercortisolaemia a factor in chronic fatigue syndrome? Hormone and Metabolic Research, 2003, 35, 4, 201-203.
Steinau, M., Rajeevan, MS., Jones, JF., Vernon, SD., Taysavang, D and Unger, ER. Use of differential display PCR (DD-PCR) to characterize exercise response in chronic fatigue syndrome (CFS.) FASEB Journal, 2003, 17 (5 SUPPL: Part 2), A1191-A1191. [Experimental Biology 2003: Meeting Abstracts]
A characteristic of CFS subjects is that exercise tolerated by controls induces profound illness. We used DD-PCR to profile the exercise response of peripheral blood mononuclear cells (PBMC). DD-PCR was done with 16 primer combinations using RNA from PBMC collected before and 24 hrs after exercise. Differentially expressed bands were excised, reamplified and sequenced.
BLAST determined the identity and functional categories of bands with <10% ambiguous bases. Of 57 bands, 6 were baseline differences between CFS and controls and the remainder were exercise responsive; 12 were changed in CFS and controls (7 inverse direction in CFS), 10 changed in control only, and 29 in CFS only.
BLAST failed to match 17/57 sequences, and half of those identified had unknown function. Most genes with known functions belonged to DNA replication/modification (15%), immune function (20%), metabolism (20%), and transcription/translation (30%). In CFS, 5/7 genes upregulated by exercise were assigned to transcription/ translation and immune functions whereas 17/22 down-regulated by exercise were novel expressed sequences. Few baseline differences were identified between CFS and controls. Overall a high proportion of differentially regulated genes were of unknown function or completely novel. This emphasizes the importance of DD-PCR as a tool for disease-specific marker discovery.
Tahmaz, N., Soutar, A and Cherrie, JW. Chronic fatigue and organophosphate pesticides in sheep farming: A retrospective study amongst people reporting to a UK pharmacovigilance scheme. Annals of Occupational Hygiene, 2003, 47, 4, 261-267.
Tanaka, S., Kuratsune, H., Hidaka, Y., Hakariya, Y., Tatsumi, KI., Takano, T., Kanakura, Y and Amino, N. Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. International Journal of Molecular Medicine, 2003, 12, 2, 225-230.
The disturbance of the central nervous system and immunological abnormalities have been suggested in patients with CFS. We focused on immunological abnormalities against neurotransmitter receptors.
Using a sensitive radioligand assay, we examined serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 (CHRM1), mu-opioid receptor (OPRM1), 5-hydroxytryptamine receptor 1A (HTR1A), and dopamine receptor D2 (DRD2) in patients with CFS (n=60) and results were compared with those in patients with autoimmune disease (n=33) and in healthy controls (n=30).
The mean anti-CHRM1 antibody index was significantly higher in patients with CFS (p<0.0001) and autoimmune disease (p<0.05) than that in healthy controls, and positive reaction was found in 53.3% of patients with CFS. Anti-OPRM1 antibodies, anti-HTR1A antibodies, and anti-DRD2 antibodies were found in 15.2, 1.7, and 5.0% of patients with CFS, respectively. Anti-nuclear antibodies were found in 56.7% (34/60) of patients with CFS, but anti-nuclear antibody titers did not correlate with the activities of the above four autoantibodies. The patients with positive autoantibodies to CHRM1 had a significantly higher mean score (1.81) of 'feeling of muscle weakness' than negative patients (1.18) among CFS patients (p<0.01). Higher scores on 'painful node', 'forgetfulness', and 'difficulty thinking' were also found in CFS patients with anti-CHRM1 antibodies but did not reach statistical significance.
In conclusion, autoantibodies to CHRM1 were detected in a large number of CFS patients and were related to CFS symptoms. Our findings suggested that subgroups of CFS are associated with autoimmune abnormalities of CHRM1.
Van Hoof, E., Cluydts, R and De Meirleir K. Atypical depression as a secondary symptom in chronic fatigue syndrome. Medical Hypotheses, 2003, 61, 1, 52-55.
Through anecdotal evidence, atypical depression appears to be common in CFS. Recent developments in psychobiology underscore the role of the acute phase response and its associated sickness behavior in affective disorders. The authors hypothesize that atypical depression is related to the sickness (e.g. infection) rather than an affective disorder as shown by anecdotal evidence in CFS.
VanNess, JM., Snell, CR., Stevens, SR., Phippen, SG and Strayer, DR. Impairment and gender differences in chronic fatigue syndrome. FASEB JOURNAL, 2003, 17, 5, Pt 2, A940-A940.
More women than men are diagnosed with CFS often leading to unequal gender distribution among research subjects. This can be problematic when exercise capacity is a dependent variable and gender data are pooled. Oxygen uptake in women is usually lower than in men. When not controlled or, this gender difference may confound research results. This study compares exercise responses of male and female CFS patients controlling for age and exercise capacity.
Cardiopulmonary exercise tests from 50 male and 50 female CFS patients, matched for age and level of functional impairment, were analysed for gender differences using the dependent variables: body mass index (BMI); respiratory quotient; rating of perceived exertion; increase in heart rate; increase in systolic blood pressure (SBP); and percentage of predicted oxygen uptake (%VO2 peak).
As follow-up to a significant multivariate effect (p< 0.001), univariate analyses found the females to have values significantly higher than the males for %VO2 peak. BMI and increase in SBP were significantly higher for the males (all p<0.01). No other significant differences were observed. The women achieved a peak VO2 closer to their maximal predicted values which raises the issue of possible gender bias in disability classification.
These results could be explained by fitness factors unrelated to CFS. Alternately, exercise mediated endocrinological abnormalities that may differentiate between CFS patients and healthy controls could also vary as a function of gender within the CFS population. Reasons for the observed differences notwithstanding, these results illustrate the importance of considering gender as a variable when designing and conducting CFS research.
VARI0US Medically unexplained symptoms. Journal of the Royal Society of Medicine, 2003, 96, 368-369.
Five letters responding to Page and Wessely (ibid, 223-227). Goodare notes the value of self-help groups, and challenges the claim that they can encourage inappropriate illness behaviour. Goadby asks whether patients are always adequately investigated before being classed as 'medically unexplained', and raises the possibility that some may be misdiagnosed. Skinner argues that such illnesses may not be dealt with by a generalists as these are no longer very common. Mendel requests that doctors continue to use recognisable terminology, rather than terms such as medically unexplained symptoms or MUS. Yodiaken also raises the issue of misdiagnosis.
Two letters supporting Page and Wessely were published in a later issue (p. 422, Mackie and Frank, Kumar).
Watson, NF., Kapur, V., Arguelles, LM., Goldberg, J., Schmidt, DF., Armitage, R and Buchwald, D. Comparison of subjective and objective measures of insomnia in monozygotic twins discordant for chronic fatigue syndrome. Sleep, 2003, 26, 3, 324-328.
The aim of this study was examine the objective and subjective measures of insomnia in CFS. Subjects were 22 pairs of monozygotic twins where 1 member of the pair had CFS and the other did not.
The 22 twin pairs completed a Sleep Disorders Questionnaire, overnight polysomnography, and a postpolysomnography sleep survey. Mean and percent differences in the sleep measures were compared between the CFS and healthy twins using matched-pair methods of analysis. Compared with their healthy co-twins, the CFS twins more frequently endorsed 8 subjective measures of insomnia and poor sleep (all p < or = 0.05). However, the CFS and healthy twins did not differ in objective polysomnographic measures of insomnia, including sleep latency, total sleep time, sleep efficiency, arousal number, arousal index, hypnogram awakenings, rapid eye movement (REM)-sleep latency, and percent stages 1, 2, and 3-4 (delta). Per cent stage REM sleep was increased in the CFS twins compared with the healthy twins (27.7% vs. 24.4%, p < or = 0.05). On the postpolysomnography survey, CFS twins reported that they had slept fewer hours (6.2 vs. 6.7; p < or = 0.05), and were less well rested (p < or = 0.001) compared to their co-twins.
CFS patients had worse subjective sleep than their co-twins despite little objective data supporting this discrepancy, suggesting they suffer from an element of sleep-state misperception. The higher percentage of REM sleep in the CFS twins implies that REM sleep may play a role in this illness.
Jason, LA., Fennell, PA and Taylor, RR. Handbook of Chronic Fatigue Syndrome. New Jersey: John Wiley & Sons. 2003. HB. 794 pp. $90.
Overview of CFS, with little discussion of the confusion caused by the name and lack of sound criteria, and with a section on treatment which is dominated by a generally uncritical approach to CBT. Good in parts but inconsistent, and far too biased for this reviewer. Disappointing.
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