Objective: We examined the blood of 48 North American chronic fatigue syndrome (CFS) patients subsequently diagnosed with Lyme disease (Borrelia burgdorferi infection) and compared these with 50 North American CFS patients without evidence of Borrelia burgdorferi infections for presence of Mycoplasma species coinfections using forensic polymerase chain reaction. Results: We found that 68.75% of CFS/Lyme patients show evidence of mycoplasma coinfections (odds ratio [OR] = 41.8; confidence limits [CL] = 11.3–155; and p < .001) compared with controls, whereas 50% of CFS patients without a diagnosis of Lyme disease show Mycoplasma coinfections (OR = 19.0; CL = 5.3–69; and p < .001) compared with controls. Because CFS patients without a diagnosis of Lyme disease have a high prevalence of one of four Mycoplasma species and a majority show evidence of multiple infections, we examined CFS/Lyme patients' blood for various Mycoplasma species. We found that CFS patients with Lyme disease mostly had single species Mycoplasma infections (OR = 31.7; CL = 8.6–116; and p < .001) with a preponderance of Mycoplasma fermentans infections (50% of patients; OR = 59.0; CL = 7.6–460; and p < .001), whereas the most commonly found Mycoplasma species in CFS patients without Lyme disease was Mycoplasma pneumoniae(34% of patients; OR = 14.94; CL = 3.3–69; and p < .001). Conclusions: The results indicate that a subset of CFS patients show evidence of infection with Borrelia burgdorferi, and a large fraction of these patients were also infected with Mycoplasma fermentans and to a lesser degree with other Mycoplasma species.
Objective: This article reviews issues involving the name of an illness, chronic fatigue syndrome (CFS), along with flawed epidemiologic approaches, which may have further contributed to the diagnostic skepticism and stigma that those with CFS encounter. Methods: Patient groups around the world are currently engaged in a major effort to rename this syndrome as either myalgic encephalomyelitis or myalgic encephalopathy, to undo the negative effects of the name previously given to this illness by scientists. Moreover, during the last 15 years, estimated rates of CFS have dramatically increased in both Great Britain and the United States. Results: We suggest that the increases in both the United States and Great Britain are due to a broadening of the case definition to additionally include cases with primary psychiatric conditions. Conclusion: Using a broad or narrow definition of CFS will have crucial influences on CFS epidemiologic findings, on rates of psychiatric comorbidity, and ultimately on the likelihood of finding a biological marker and identified etiology.
Objective: The current study examined cognitive function, major depressive disorder (MDD), and apathy construct symptoms in a large multi-site surveillance study of chronic fatigue syndrome conducted by the Centers for Disease Control and Prevention. Method: Subjects underwent neuropsychological testing and were administered the Diagnostic Interview Schedule to establish psychiatric diagnoses. Questions in the Beck Depression Inventory relating to motivation were used to develop an apathy construct. Results: Neuropsychological test results showed impairment in multiple cognitive domains in over 25% of the cohort, and raised proportions of outliers in motor and executive function. Memory complaints were not associated with tests of memory function. The apathy construct rather than MDD was associated with impaired cognition. Conclusions: Impaired cognition in chronic fatigue does not appear to be associated with MDD but rather with endorsement of construct symptoms. Similar associations were reported in medical conditions with known etiologies. These results suggest a potential biological basis for apathy construct symptoms.
Objective: Understanding how nonpharmacologic interventions differentially affect the subgroups of patients with chronic fatigue syndrome (CFS) might provide insights into the pathophysiology of this illness. In this exploratory study, baseline measures of normal versus abnormal cortisol were compared on a variety of immune markers and other self-report measures. Normal versus abnormal cortisol ratings were used as predictors in a nurse-delivered nonpharmacologic intervention. Methods: Participants diagnosed with CFS were assigned to 6-month nonpharmacologic interventions. Individuals were classified as having abnormal or normal cortisol levels on the basis of scores over the five testing times. Cortisol levels were considered abnormal if they continued to rise, were flat, or were at abnormally low over time. Results: Across interventions, those with abnormal cortisol at the baseline appeared not to improve over time, whereas those with normal baseline cortisol evidenced improvements on a number of immunologic and self-report measures. Conclusion: It appears that, in subgroups of individuals with CFS, baseline cortisol markers are associated with outcome trajectories for nonpharmacologic treatment trials. The implications of these findings are discussed.
An epidemiological case-definition was developed to distinguish myalgic encephalomyelitis/chronic fatigue syndrome from other chronic fatiguing conditions by evaluating the discriminatory potential of different criteria from previous definitions. A two-part model was derived using consensus and discriminant analytic approaches. The optimal discriminators for the first part were severe debilitating fatigue affecting physical and mental functioning, a reduction in activity to less than 50% of the patient's premorbid activity level, and muscle discomfort (sensitivity 92%, specificity 66%). The variables for the second part included a reduction in activity to less than 50% of the patient's premorbid activity, myalgia, generalized muscle weakness, migratory arthralgia, and swollen lymph nodes (sensitivity 77%, specificity 88%).
Fatigue is a central component of many diseases and illnesses. Fatigue of unknown etiology and pathophysiology lasting more than six months, together with at least four out of eight specified symptoms, is termed chronic fatigue syndrome (CFS). Several causes have been suggested for the illness, including immune dysfunction, stress, sleep disturbances and infectious agents. CFS diagnosis is currently based on selfreported symptoms. The lack of physical abnormalities and laboratory tests makes the diagnosis harder. Identification of biological illness markers would contribute to increase insight into the pathophysiology of the illness and facilitate diagnosis. Powerful methods for transcript analysis have been developed during the past decade. Microarray technology and real-time PCR are two methods commonly used to identify genes involved in disease. The identified genes are disease markers, which may be used for diagnostic purposes. Researchers involved with microarray experiments need standardization to facilitate comparisons between studies and laboratories. We show here that different RNA extraction methods can yield comparable results. Even so, only one method should be used in any one study and the ambition should be to use identical conditions for each and every experiment. CFS is not characterized by any diseased tissue, and this raises the question of what is a representative sample. The hypothesis has been raised that peripheral blood cells function as indicators for different biological processes going on throughout the human body. We show here that genes involved in psychoneuroendocrine-immune (PNI) communication can be studied using peripheral blood mononuclear cells (PBMCs). The PBMC sample can be used to study diseases, such as CFS, with unknown pathophysiology and etiology. The individual transcript expression variability in PBMCs is small and differences in gene activity due to abnormalities caused by illness or disease are larger. We expected to find only small gene expression differences, if any, between CFS patients and healthy controls. In our transcript expression studies we observed only a few differentially expressed genes. We found reduced levels of estrogen receptor β (ERβ) in CFS patients compared to healthy controls using real-time PCR. Three genes were identified using microarray technology with significant expression differences: CD83, NRK1 and BOLA1. The differences were only found between a subgroup of CFS patients, female patients with no previous infection and gradual illness onset, compared with healthy female controls. We verified the results with real-time PCR. The results indicate the need for subgrouping of the heterogeneous group of patients with fatiguing illness in search for pathogenic mechanisms. In conclusion, the difference in gene expression could contribute to some of the symptoms observed in CFS. Further studies to investigate the protein levels and cellular effects will be required to determine whether any of these genes are involved in CFS pathology. The differences in transcript expression levels could also simply be a marker for changed functions of other cellular components that are involved in CFS. In this case, the altered levels could contribute to diagnostic criteria, they may form a surrogate marker, or they may provide an entry point to identifying potential disease-causing candidate molecules for further study. LIST OF PUBLICATIONS This thesis is based on the following papers, which in the text will be referred to by their corresponding Roman numbers: I. Ojaniemi H, Evengard B, Lee DR, Unger ER and Vernon SD Impact of RNA extraction from limited samples on microarray results BioTechniques, 35(5):968-973, 2003 II. Nicholson AC, Unger ER, Mangalathu R, Ojaniemi H and Vernon SD Exploration of neuroendocrine and immune gene expression in peripheral blood mononuclear cells Molecular Brain Research, 129(1-2):193-197, 2004 III. Grans H, Nilsson P and Evengard B Gene expression profiling in the Chronic Fatigue Syndrome Journal of Internal Medicine, 258(4):388-390, 2005 IV. Grans H, Evengard B and Nilsson P Transcriptome analysis of PBMCs from patients with Chronic Fatigue Syndrome Manuscript V. Grans H, Nilsson M, Gustafsson J-A, Dahlman-Wright K and Evengard B Reduced levels of ERβ mRNA in Swedish patients with Chronic Fatigue Syndrome Submitted
This article examines the legal and scientific bases on which an exercise stress test can provide medically acceptable evidence of disability for the Chronic Fatigue Syndrome (CFS) patient. To qualify for disability benefits, a claimant must establish the existence of a serious medically determinable impairment (MDI) that causes the inability to work. The single stress test has been used to objectively establish whether a claimant can engage in “substantial gainful employment” and is an important determinant of the award or denial of benefits. A review of case law indicates problems associated with a single test protocol that may be remedied by a “test-retest” protocol. The results of a preliminary study employing this approach indicate that the test-retest protocol addresses problems inherent in a single test and therefore provides an assessment of CFS related disability consistent with both medical and legal considerations.
The present study investigated the possible association between the Chronic Fatigue Syndrome (CFS) and Obsession Compulsion (OC). A non-clinical sample of 427 volunteer Kuwaiti male and female college students was recruited. Their ages ranged from 17 to 40 years. They completed the Arabic Scale of CFS (ASCFS) and the Arabic Scale of Obsession Compulsion (ASOC). Both have good reliability and validity. Females had significantly higher mean score on the ASCFS than did their male counterparts. All the intercorrelations between the 20 items as well as the total score of the ASCFS were statistically significant (p < 0.01) with the total ASOC score in males and females. It was concluded that there is an obsessive compulsive element in CFS, and both disorders share specific common elements.
Objective: To assess the effects of an early educational intervention program's ability to alter the perceptions and attitudes of future physicians regarding chronic fatigue syndrome/fibromyalgia (CFS/FM), improve their understanding and acceptance of these diseases, make them feel more comfortable in diagnosing and treating patients.Method: Third-year medical students were surveyed before and after an educational intervention program. The three questions posed to the students in the survey were: (1) How comfortable do you feel you are in diagnosing and treating patients with CFS /FM?, (2) Do you consider CFS/FM legitimate illnesses?, and (3) Do you want to treat patients with CFS/FM?Results: The educational intervention program helped about half of the future physicians feel comfortable in diagnosing and treating patients with CFS/FM and improved by over 25% their willingness to treat patients with CFS.Conclusion: An educational intervention program appeared to improve future physicians' understanding and appreciation of CFS/FM, made them feel more comfortable diagnosing and treating these diseases, and increased their willingness to treat patients with CFS/FM.
Objective: To explore how individuals with chronic fatigue syndrome (CFS) describe their fatigue experience and examine how this differs from descriptions of fatigue in healthy controls.Methods: Fifty-two individuals with CFS and 27 controls listed words that described their fatigue. These words were grouped into 18 categories.Results: Individuals with CFS used more categories to describe their fatigue and more descriptors within each category. The most popular category used by both groups was energy depletion/physical weakness. CFS participants also experienced their fatigue as limiting their ability to function, frustrating, permanent/persistent, out of their control, depressing, and pervading all aspects of their lives. Controls reported that when they experienced fatigue, it was temporary, and they felt unmotivated, sleepy, and comfortable.Conclusion: The multidimensional descriptive pattern characterizing the fatigue of individuals with CFS differs dramatically from the experienced fatigue of healthy individuals, suggesting their “language of fatigue” has a distinctive quality.
Objective: In a sample of 47 adults with CFS, we aimed to describe patterns of service utilization, identify barriers to service access, and explore the relationship between service utilization and coping styles.Method: A questionnaire assessing service utilization frequency and barriers to service access was administered to a sample of 47 individuals with CFS. The Illness Management Questionnaire was used to assess relationships between coping styles and service utilization.Results: A Cochran's Q test of homogeneity revealed that medical and CFS self-help services were most frequently used and rehabilitation services were least frequently used. In terms of service accessibility,80.9% of participants reported at least one barrier. Lack of financial (including insurance) resources and lack of knowledge about service availability were the two most frequently reported. In terms of coping styles, symptom focusing was positively associated with use of CFS self-help services and with use of in-home services and social service agencies. Information seeking was negatively associated with use of in-home and social service agencies and with use of mental health services.Conclusion: These findings can be used by health-care professionals and advocacy-based organizations to develop programs focused on mass education campaigns for health-care providers, increase knowledge of service availability among individuals with CFS, and to understand relationships between certain types of coping styles and service preferences.
Reduced functional capacity and post-exertional malaise following physical activity are hallmark symptoms of Chronic Fatigue Syndrome (CFS). That these symptoms are often delayed may explain the equivocal results for clinical cardiopulmonary exercise testing with CFS patients. The reproducibility of VO2 max in healthy subjects is well documented. This may not be the case with CFS due to delayed recovery symptoms.Purpose: To compare results from repeated exercise tests as indicators of post-exertional malaise in CFS.Methods: Peak oxygen consumption (VO2 peak), percentage of predicted peak heart rate (HR%), and VO2 at anaerobic threshold (AT), were compared between six CFS patients and six control subjects for two maximal exercise tests separated by 24 hours.Results: Multivariate analysis showed no significant differences between control and CFS, respectively, for test 1: VO2 peak (28.4 ± 7.2 ml/ kg/min; 26.2 ± 4.9 ml/kg/min), AT (17.5 ± 4.8 ml/kg/min; 15.0 ± 4.9 ml/ kg/min) or HR% (87.0 ± 25.4%; 94.8 ± 8.8%). However, for test 2 the CFS patients achieved significantly lower values for both VO2 peak (28.9 ± 8.0 ml/kg/min; 20.5 ± 1.8 ml/kg/min, p = 0.031) and AT (18.0 ± 5.2 ml/kg/min; 11.0 ± 3.4 ml/kg/min, p = 0.021). HR% was not significantly different (97.6 ± 27.2%; 87.8 ± 9.3%, p = 0.07). A follow-up classification analysis differentiated between CFS patients and controls with an overall accuracy of 92%.Conclusion: In the absence of a second exercise test, the lack of any significant differences for the first test would appear to suggest no functional impairment in CFS patients. However, the results from the second test indicate the presence of a CFS related post-exertional malaise. It might be concluded then that a single exercise test is insufficient to demonstrate functional impairment in CFS patients. A second test may be necessary to document the atypical recovery response and protracted malaise unique to CFS.
Objective: There continues to be a shortage of clinical staff specialising in the treatment of CFS (ME). In order to access specialist care, many clients have to undertake long or difficult journeys that may exacerbate their symptoms. This exploratory study aimed to reduce these travel problems by the introduction of a Teleconference Review Clinic (TRC).Method: ATRC was booked for six CFS clients who would normally have face-to-face review by specialists 44 miles away. Questionnaires were used to elicit the views of both clients being reviewed and clinicians undertaking the review at a distance. Differences in distances travelled by clients for conventional face to face and telemedicine review were calculated and comments about the teleconference made by clients and therapists were noted.Results: There was general satisfaction with the quality of the pictures and sound during the reviews. Clinicians were able to obtain all the information required to undertake all clinical assessments. For two clients the clinical management was changed after the consultation and for one client an issue was identified that required referral to another clinician. For clients who lived nearer to the teleconference hospital, the journey saved ranged between 1 mile and 85.8 miles, the mean being 64.2 miles.Conclusion: This pilot study does suggest that telemedicine in this area of medicine is logistically viable and effective, and indicates that a larger study is needed.
Background: It is uncertain how much fatigue is related to weight in patients with chronic fatigue syndrome (CFS).Objective: To assess the association of body mass index (BMI) and fatigue in CFS patients.Methods: Consecutive patients seen in a referral-based specialty clinic were eligible if they met CFS criteria and had completed required measures. Fatigue measures were the vitality subscale of the Medical Outcomes Short-Form 36 and the global fatigue index from the Multidimensional Assessment of Fatigue.Results: In women, there was no relationship between BMI and vitality subscale or global fatigue index scores (P = 0.99 and P = 0.44). For men, vitality subscale scores significantly decreased as BMI increased (P = 0.02).Conclusions: In CFS patients, the prevalence of obesity was low despite risk factors for weight gain. Fatigue severity and BMI were unrelated in women with CFS, but this relationship may differ for men.Key Words: Chronic fatigue syndromefibromyalgiafatigueweight
Patients affected by chronic fatigue syndrome (CFS) characteristically show easy and unexplained fatigue after minimal exertion that does not resolve with rest and is associated with specific symptoms lasting for more than six months. Cardiopulmonary exercise testing is a valid procedure for determining functional capacity in patients with CFS. We compare cardioventilatory adaptation to exercise between a group of eighty-five consecutive women patients affected by CFS and a group of fifteen healthy women extremely sedentary individuals, with the use of maximum incremental exercise testing on a cycle ergometer and arm ergometer, assessing possible differences. The majority of values achieved at peak exhaustive exercise were significantly lower in CFS patients than controls, including the percentage of maximum oxygen uptake in arm physical test (37.4±10.0% in CFS vs. 58.9± 15.8% in controls) and leg physical test (53.4±15.0% in CFS patients vs. 76.2 ± 18.0%in controls).In conclusion, the CFS group shows a lower work capacity in arm or leg exercise that would not be justified exclusively by their personal characteristics or deconditioning.Key Words: Chronic fatigue syndromemaximal oxygen uptakelactate
Objective: Patients with chronic fatigue syndrome (CFS) have substantial deficits in functional capacity, but the course of these deficits over time has not often been studied. This study measured functional capacity on three occasions over a decade, in patients with CFS.Methods: The study was a longitudinal cohort study, and employed the Medical Outcomes Study Short Form-36 (SF-36) instrument to assess physical and mental/emotional functional status.Results: Physical function, as reflected in several different scales, improved modestly but significantly over time, particularly for patients aged 18-60 years and for women. Mental/emotional function was not substantially impaired at the outset of the study, and did not change over time.Conclusion: This study found that physical function tended to improve formany patients over time, despite the fact that they were aging. Physical function did not deteriorate with time.
Personality may play a role in the predisposition, the precipitation and/or the maintenance of the CFS. Thirty-six consecutively examined female patients hospitalised for a sleep workup, filled out a Temperament and Character Inventory (TCI) questionnaire. A MANOVA compared the patientswith a control group of femalesmatched for age. Significant scores were obtained for dimensions such as Harm Avoidance, Reward Dependence, and Self-Directedness. However, the only subdimension of Harm Avoidance that proved significantly higher in CFS than in controls was "Fatigability,"; which is likely to overlap with the core CFS symptom. All in all, the personality structure does not appear to play a major role in the CFS.
There is controversy regarding the incidence and significance of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in chronic fatigue syndrome (CFS) and fibromyalgia (FM). Studies that utilize central acting stimulation tests, including corticotropin-releasing hormone (CRH), insulin stress testing (IST), d-fenfluramine, ipsapirone, interleukin-6 (IL-6) and metyrapone testing, have demonstrated that HPA axis dysfunction of central origin is present in a majority of these patients. However, ACTH stimulation tests and baseline cortisol testing lack the sensitivity to detect this central dysfunction and have resulted in controversy and confusion regarding the incidence of HPA axis dysfunction in these conditions and the appropriateness of treatment. While both CFS and FM patients are shown to have central HPA dysfunction, the dysfunction in CFS is at the pituitary-hypothalamic level while the dysfunction in FM is more related to dysfunction at the hypothalamic and supra-hypothalamic levels. Because treatment with low physiologic doses of cortisol (<15 mg) has been shown to be safe and effective and routine dynamic ACTH testing does not have adequate diagnostic sensitivity, it is reasonable to give a therapeutic trial of physiologic doses of cortisol to the majority of patients with CFS and FM, especially to those who have symptoms that are consistent with adrenal dysfunction, have low blood pressure or have baseline cortisol levels in the low or low-normal range.
Objective: To examine the influence of body mass index (BMI) and weight change on fatigue severity and failure to recover in individuals with acute infectious mononucleosis.Methods: We prospectively studied 148 individuals presenting with a positive monospot test. We obtained measured weights and vitality subscale scores from the Short Form-36 Health Survey (SF-36) at the index visit and at 6 months.Results: The mean age of the participants was 21 years and 24% were overweight or obese. During acute illness, overweight and obese participants had an adjusted odds ratio for low vitality scores of 2.9 (confidence interval 1.2–7.1) compared to normal weight subjects. Neither index BMI nor 6-month weight gain was significantly associated with prolonged fatigue or failure to recover.Conclusion: Overweight and obese patients with acute infectious mononucleosis are more likely to experience severe fatigue. In contrast, neither baseline weight nor weight gain appear to impede recovery.
