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Koelle, DM., Barcy, S., Huang, ML., Ashley, RL., Corey, L., Zeh, J., Ashton, S and Buchwald, D. Markers of viral infection in monozygotic twins discordant for chronic fatigue syndrome. Clinical Infectious Diseases, 2002, 35, 5, 518-525.
To estimate the prevalence of viruses associated with CFS and to control for genetic and environmental factors, we conducted a co-twin control study of 22 monozygotic twin pairs, of which one twin met criteria for CFS and the other twin was healthy.
Levels of antibodies to human herpesvirus (HHV)-8, cytomegalovirus, herpes simplex virus 1 and 2, and hepatitis C virus were measured. Polymerase chain reaction (PCR) assays for viral DNA were performed on peripheral blood mononuclear cell specimens to detect infection with HHV-6, HHV-7, HHV-8, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, varicella zoster virus, JC virus, BK virus, and parvovirus B19. To detect lytic infection, plasma was tested by PCR for HHV-6, HHV-8, cytomegalovirus, and Epstein-Barr virus DNA, and saliva was examined for HHV-8 DNA.
For all assays, results did not differ between the group of twins with CFS and the healthy twins.
Lerner, MA., Beqaj, SH., Deeter, RG and Fitzgerald, JT. IgM serum antibodies to human cytomegalovirus nonstructural gene products p52 and CM2 (UL44 and UL57) are uniquely present in a subset of patients with chronic fatigue syndrome. In Vivo, 2002, 16, 3, 153-159.
Human cytomegalovirus (HCMV) IgM serum antibodies to two non-structural gene products UL44 and UL57 (p52 and CM2) were assayed in patients with the diagnosis of the CFS according to criteria established by the CDC.
A subset of 16 CFS patients demonstrated HCMV IgG, but no HCMV IgM serum antibodies to conformational structural HCMV antigens (designated, V). By convention, these findings are interpreted to indicate only a remote HCMV infection. However, HCMV IgM p52 and CM2 antibodies were uniquely present in these 16 CFS patients.
Other CFS patients with similar HCMV (V) IgG antibodies (18 patients), non-fatigued HCMV (V) IgG-positive control patients (18 patients), random HCMV (V) IgG-positive control patients from a clinical laboratory (26 patients), and non-fatigued HCMV (V) IgG-negative control patients (15 patients) did not have HCMV, IgM p52 or CM2 serum antibodies (p<0.05).
Control HCMV (V) IgG-positive patients had no serum IgM HCMV (V) antibodies to conventional structural HCMV (V) antigen. Thus, 77 various control patients did not contain IgM p52 or CM2 serum antibodies. The presence of IgM p52 and/or CM2 HCMV serum antibodies in this subset of CSF-specific patients may detect incomplete HCMV multiplication in which a part of the HCMV protein-coding content of the HCMV genome is processed, but remains unassembled.
These findings suggest that the presence of HCMV IgM p52 and CM2 serum antibodies may be a specific diagnostic test for the diagnosis of a subset of CFS patients. Further, these data suggest an etiologic relationship for HCMV infection in this group of CFS patients.
Arnold, MC., Papanicolaou, DA., O'Grady, JA., Lotsikas, A., Dale, JK., Straus, SE and Grafman, J. Using an interleukin-6 challenge to evaluate neuropsychological performance in chronic fatigue syndrome. Psychological Medicine, 2002, 32, 6, 1075-1089.
Individuals with acute infections experience a range of symptoms including fatigue, malaise, muscle aches, and difficulties with concentration and memory that are usually self-limited. This cluster of symptoms is otherwise, similar to those that characterize CFS. The aim of this study was to evaluate the cognitive and psychological functioning of CFS patients and normal controls (NCs) when they both were experiencing acute influenza-like symptoms. To induce influenza-like symptoms, we administered interleukin-6 (IL-6), a cytokine that temporarily activates the acute phase im-munological and endocrine responses.
METHODS: Nineteen patients with CFS (CDC criteria '94) and ten normal controls (NCs) completed routine clinical evaluations, neuropsychological tests of short-term memory, selective attention, and executive control, plus self-ratings of somatic symptoms and psychological mood before, shortly following, and 1 day after IL-6 administration.
RESULTS: CFS patients consistently reported more somatic symptoms... Both groups somatic symptoms increased during the IL-6 challenge, but the CFS patients' symptoms increased more rapidly than controls. Their temperature was also raised 1.5 hours after the injection. A day later, scores were below baseline ones, though fatigue and malaise remained, suggesting improvement in cell-mediated immunity. In general, the CFS patients performed similarly to NCs on the cognitive measures before, during, and after the IL-6. In contrast to predictions, IL-6 provocation did not impair the cognitive performance of either CFS patients or NCs.
CONCLUSIONS: The IL-6 provocation exacerbated the patients self-reported symptoms but did not reveal notable cognitive impairments between patients and controls during cytokine-induced acute influenza-like symptoms.
Kuratsune, H., Yamaguti, K., Lindh, G., Evengard, B., Hagberg, G., Matsumura, K., Iwase, M., Onoe, H., Takahashi, M., Machii, T., Kanakura, Y., Kitani, T., Langstrom, B and Watanabe Y. Brain regions involved in fatigue sensation: reduced acetylcarnitine uptake into the brain. Neuroimage, 2002, 17, 3, 1256-1265.
Fatigue is an indispensable sense for ordering rest. However, the neuronal and molecular mechanisms of fatigue remain unclear. CFS with long-lasting fatigue sensation seems to be a good model for studying these mechanisms underlying fatigue sensation. Recently, we found that most patients with CFS showed a low level of serum acetylcarnitine, which correlated well with the rating score of fatigue, and that a considerable amount of acetyl moiety of serum acetylcarnitine is taken up into the brain.
Here we show by metabolite analysis of the mouse brain that an acetyl moiety, taken up into the brain through acetylcarnitine, is mainly utilized for the biosynthesis of glutamate. When we studied the cerebral uptake of acetylcarnitine by using [2-11C]acetyl-L-carnitine in 8 patients with CFS (CDC criteria '94, no major depression, all with low levels of serum acylcarnitine) and in 8 normal age- and sex-matched controls, the PET scans showed a significant decrease in several regions of the brains of the patient group, namely, in the prefrontal (Brodmann's area 9/46d) and temporal (BA21 and 41) cortices, anterior cingulate (BA24 and 33), and cerebellum.
These findings suggest that the levels of biosynthesis of neurotransmitters through acetylcarnitine might be reduced in some brain regions of chronic fatigue patients and that this abnormality might be one of the keys to unveiling the mechanisms of the chronic fatigue sensation.
Puri, BK., Counsell, SJ., Zaman, R., Main, J., Collins, AG., Hajnal JV and Davey, NJ. Relative increase in choline in the occipital cortex in chronic fatigue syndrome. Acta Psychiatrica Scandinavica, 2002, 106, 3, 224-226.
Objective: To test the hypothesis that CFS is associated with altered cerebral metabolites in the frontal and occipital cortices.
Method: Cerebral proton magnetic resonance spectroscopy (1H MRS) was carried out in eight patients with CFS (CDC criteria '94) and eight age- and sex-matched healthy control subjects. Spectra were obtained from 20 x 20 x 20 mm3 voxels in the dominant motor and occipital cortices using a point-resolved spectroscopy pulse sequence.
Results: The mean ratio of choline (Cho) to creatine (Cr) in the occipital cortex in CFS (0.97) was significantly higher than in the controls (0.76; p=0.008). No other metabolite ratios were significantly different between the two groups in either the frontal or occipital cortex. In addition, there was a loss of the normal spatial variation of Cho in CFS.
Conclusion: Our results suggest that there may be an abnormality of phospholipid metabolism in the brain in CFS.
Pall, ML. Levels of nitric oxide synthase product Citrulline are elevated in sera of chronic fatigue syndrome patients. Journal of Chronic Fatigue Syndrome, 2002, 10, (3/4), 37-41.
Serum levels of citrulline, a product of nitric oxide synthase activity, were measured in 36 patients with CFS (CDC criteria '94) and 16 controls to determine whether synthase activity may be elevated in CFS patients. Serum citrulline levels were found to be significantly elevated in CFS patients and, in addition, there was a trend towards higher levels in CFS patients with stronger symptoms. These results provide support for the view that nitric oxide synthase activity tends to be elevated in CFS patients, thus supporting a prediction of the elevated nitric oxide/peroxynitrite theory of CFS etiology.
Richardson, J. Toxins and immunity in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2002, 10, (3/4), 43-50.
In this paper, Dr. Richardson illustrates links between exposure, absorption and effects of viruses, bacteria, and inorganic toxins, and their toll on the immune system, as potential causes of chronic symptomatology as seen in CFS.
Ohashi, K., Yamamoto, Y and Natelson, B. Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome. Physiology and Behaviour, 2002, 77, 1, 39.
Post-exertional exacerbation of symptoms is one of the major characteristics of CFS. In this study, we evaluated the hypothesis that disturbances in circadian chronobiological regulation may play a role in generating this phenomenon.
We recorded physical activity for 6-day periods in 16 women (10 CFS and 6 sedentary healthy controls, CON) before and after performing a maximal treadmill test. We calculated activity rhythms by computing autocorrelation coefficients by cutting 1 day apart from the data as a template and sliding it sequentially through each of the other days; all of 6 days were used as the templates.
The peak value of autocorrelation coefficient (R) and the time between peak R's (circadian period, CP) were calculated. CFS patients had a lengthening (p<.05) of mean circadian period (MCP) that was longer than 24 h (p<.05), while MCP in CON remained unchanged. No difference was found in the standard error of each subject's MCP (circadian period variability, CPV) before and after exercise for both groups.
We interpret this increase in circadian rest-activity period seen in CFS patients following exercise to indicate that exhaustive exercise interferes with normal entrainment to 24-h zeitgeber(s). This effect may be associated in part with the common patient complaint of symptom worsening following exertion.
Timmers, HJ., Wieling, W., Soetekouw, PM., Bleijenberg, G., Van Der Meer, JW and Lenders, JW. Hemodynamic and neurohumoral responses to head-up tilt in patients with chronic fatigue syndrome. Clinical Autonomic Research, 2002, 12, 4, 273-280.
BACKGROUND: Data on the prevalence of orthostatic intolerance (OI) in patients with CFS are limited and controversial. We tested the hypothesis that a majority of CFS patients exhibit OI during head-up tilt.
METHODS: Hemodynamic and neurohumoral responses to 40 minutes of head-up tilt were studied in 36 patients with CFS (CDC criteria '94) and 36 healthy controls. Changes in stroke volume, cardiac output and peripheral vascular resistance were estimated from finger arterial pressure waveform analysis (Modelflow). Blood samples were drawn before and at the end of head-up tilt for measurement of plasma catecholamines.
RESULTS: At baseline, supine heart rate was higher in CFS patients (CFS: 66.4 +/- 8.4 bpm; controls: 57.4 +/- 6.6 bpm; p< 0.001) as was the plasma epinephrine level (CFS: 0.11 +/- 0.07 nmol/l; controls: 0.08 +/- 0.07 nmol/l: p=0.015). An abnormal blood pressure and/or heart rate response to head-up tilt was seen in 10 (27.8%) CFS patients (6 presyncope, 2 postural tachycardia, 2 tachycardia and presyncope) and 6 (16.7%, p=0.26) controls (5 presyncope, 1 tachycardia, 2 tachycardia and presyncope). Head-up tilt-negative CFS patients showed a larger decrease in stroke volume during tilt (-46.9 +/- 10.6) than head-up tilt-negative controls (-40.3 +/- 13.6 %, p=0.008). Plasma catecholamine responses to head-up tilt did not differ between these groups.
CONCLUSION: Head-up tilt evokes postural tachycardia or (pre)syncope in a minority of CFS patients. The observations in head-up tilt-negative CFS patients of a higher heart rate at baseline together with a marked decrease in stroke volume in response to head-up tilt may point to deconditioning.
Cresswell, C and Chalder, T. Underlying self-esteem in chronic fatigue syndrome. Journal of Psychosomatic Research, 2002, 53, 3, 755-761.
Objective: It has been suggested that people with CFS have low self-esteem; however, this is not necessarily apparent when self-esteem is measured overtly. This study is the first to investigate underlying self-esteem using information-processing measures and overtly administered measures of self-esteem with this population.
Methods: The study comprised 68 participants (24 CFS, 24 healthy volunteers, and 20 chronic illness volunteers). A Self-Statements Questionnaire (SSQ) and an Emotional Stroop Test (EST) using neutral, positive, and negative trait words were administered.
Results: Patients with CFS reported lower self-esteem than the two comparison groups on overt measures. Overt responses, however, did not fully account for the full extent of the interference effect from the negative word Stroop compared to the positive word Stroop.
Conclusion: In contrast to previous studies, participants with CFS reported lower levels of self-esteem on overt measures than two comparison groups. It is suggested, however, that the extent to which participants reported low self-esteem did not fully reflect their underlying low self-esteem and that this may result from the use of rigidly held defence mechanisms. Further use of information-processing measures, in contrast to relying only on self-report measures, is advocated for future research.
Morriss, RK., Robson, MJ and Deakin, JFW. Neuropsychological performance and noradrenaline function in chronic fatigue syndrome under conditions of high arousal. Psychopharmacology (Berl), 2002, 163, 2, 166-173.
RATIONALE. Subjective and objective impairments in neuropsychological function have been reported in CFS patients under conditions of high arousal. These impairments may reflect impaired central noradrenaline function such as impaired post-synaptic alpha-2 adrenoceptor function.
OBJECTIVES. To determine whether high-dose clonidine has greater agonist effects at central post-synaptic alpha-2 receptors in CFS patients than controls under conditions of high arousal. As a result clonidine may reverse neuropsychological deficits underlying symptoms of poor concentration and memory.
METHODS. High-dose clonidine (2.5 mg/kg) and placebo challenge tests were given in random order to ten medication-free CFS patients without anxiety disorders, depressive disorders or migraine and ten matched healthy controls under the same stressors (timed neuropsychological testing, venous sampling, intravenous drug administration). Growth hormone, cortisol, blood pressure, pulse rate, visual analogue scales of subjective neuropsychological performance and the performance on several tests from a computerised neuropsychological battery were measured.
RESULTS. In CFS patients versus controls, clonidine enhanced both growth hormone (p=0.028) and cortisol release (p=0.021) and increased speed in the initial stage of a planning task (p=0.023). There were no other differences between CFS patients and controls on hormonal, physiological, symptomatic or neuropsychological measures.
CONCLUSIONS. Under conditions of high arousal, CFS patients may display supersensitive central post-synaptic alpha-2 adrenoceptor function associated with the release of cortisol and growth hormone and initial thinking time in planning tasks.
Torres-Harding, SR., Jason, LA., Cane, V., Carrico, A and Taylor, RR. Physicians' diagnoses of psychiatric disorders for people with chronic fatigue syndrome. International Journal of Psychiatry in Medicine, 2002, 32, 2, 109-124.
OBJECTIVE: To examine rates of psychiatric diagnoses given by patients' primary or regular physicians to persons with CFS, persons with psychiatrically explained fatigue, and a control group. Physicians' psychiatric diagnosis and participants' self-reported psychiatric diagnoses were compared to lifetime psychiatric diagnoses as measured by a structured psychiatric interview.
METHOD: Participants were recruited as part of a community-based epidemiology study of CFS. Medical records of 23 persons with CFS, 25 persons with psychiatrically explained chronic fatigue, and 19 persons without chronic fatigue (controls) were examined to determine whether their physician had given a diagnosis of mood, anxiety, somatoform, or psychotic disorder. Lifetime psychiatric status was measured using the Structured Clinical Interview for the DSM-IV (SCID). Participants' self reports of specific psychiatric disorders were assessed as part of a detailed medical questionnaire.
RESULTS: Physicians' diagnosis of a psychiatric illness when at least one psychiatric disorder was present ranged from 40 percent in the psychiatrically explained group, 50 percent in the control group, and 64.3 percent in the CFS group. Participants in the psychiatrically explained group were more accurate than physicians in reporting the presence of a psychiatric disorder, and in accurately reporting the presence of a mood or anxiety disorder.
CONCLUSIONS: The present investigation found underrecognition of psychiatric illness by physicians, with relatively little misdiagnosis of psychiatric illness. Physicians had particular difficulty assessing psychiatric disorder in those patients whose chronic fatigue was fully explained by a psychiatric disorder. Results emphasized the importance of using participant self report as a screening for psychiatric disorder.
Van Houdenhoven, B., Neerinckx, A., Onghena, A., Vingerhoets, A., Lysens, R and Vertommen, H. Daily hassles reported by chronic fatigue syndrome and fibromyalgia patients in tertiary care: a controlled quantitative and qualitative study. Psychotherapy and Psychosomatics, 2002, 71, 4, 207-213.
This study aimed at providing insight in the frequency, emotional impact and nature of daily hassles, experienced by patients suffering from CFS and/or fibromyalgia (FM), compared with patients with a chronic organic disease.
One hundred and seventy-seven CFS/FM patients, 26 multiple sclerosis (MS) and 26 rheumatoid arthritis (RA) patients were investigated within 2-6 months after diagnosis. All patients completed a self-report questionnaire assessing daily hassles and associated distress, a visual analogue scale assessing fatigue and pain and a depression and anxiety questionnaire.
CFS/FM patients show a higher frequency of hassles, higher emotional impact and higher fatigue, pain, depression and anxiety levels compared with MS/RA patients. Three hassle themes dominate in the CFS/FM group: dissatisfaction with oneself, insecurity and a lack of social recognition. In contrast, hassles reported by MS/RA patients show a much larger diversity and are not focused on person-dependent problems.
Patients recently diagnosed as suffering from CFS and/or FM are highly preoccupied and distressed by daily hassles that have a severe impact on their self-image, as well as their personal, social and professional functioning. An optimal therapeutic approach of CFS and FM should take account of this heavy psychosocial burden, which might refer to core themes of these patients' illness experience.
Brimacombe, M., Helmer, D and Natelson, BH. Clinical differences exist between patients fulfilling the 1988 and 1994 case definitions of chronic fatigue syndrome. Journal of Clinical Psychology in Medical Settings, 2002, 9, 309-314.
Despite the existence of 2 different case definitions for CFS, little data exist to evaluate how each performs. We evaluated the symptom patterns* of patients fulfilling either the more demanding 1988 or the less demanding 1994 case definitions of CFS over an 11-year period from 1991 to 2001 (N=200). Factor analysis identified 3 factors: muscular-skeletal, viral, and sleep/memory symptom factors accounting for significant variation in the data. Further discriminant analysis showed that the first 2 factors and a self-reported measure of decrease in activity alone gave 91% accuracy in the placement of patients into their respective case definitions. This analysis did indicate that both case definitions were capturing the same broad group of patients. However, the patients in the 1994 group do not endorse infectious-type symptoms as often or to the same degree of severity as those in the 1988 group. This may mean that infection as a cause of CFS is more likely in patients fulfilling the earlier, more demanding case definition.
Brimacombe, M., Helmer, DA and Natelson, BH. Birth order and its association with the onset of chronic fatigue syndrome. Human Biology, 2002, 74, 4, 615-620.
CFS is a medically unexplained illness that is diagnosed on the basis of a clinical case definition; so it probably is an illness with multiple causes producing the same clinical picture. One way of dealing with this heterogeneity is to stratify patients based on illness onset.
We hypothesized that either the whole group of CFS patients or that group which developed CFS gradually would show a relationship with birth order, while patients who developed CFS suddenly, probably due to a viral illness, would not show such a relationship. We hypothesized the birth order effect in the gradual onset group because those patients have more psychological problems, and birth order effects have been shown for psychological characteristics. We compared birth order in our CFS patients (modified CDC criteria '94) to that in a comparison group derived from U.S. demographic data.
We found a tendency that did not reach formal statistical significance for a birth order effect in the gradual onset group, but not in either the sudden onset or combined total group. However, the birth order effect we found was due to relatively increased rates of CFS in second-born children; prior birth order studies of personality characteristics have found such effects to be skewed toward first-born children. Thus, our data do support a birth order effect in a subset of patients with CFS. The results of this study should encourage a larger multicenter study to further explore and understand this relationship.
Lindal, E., Stefansson, JG and Bergmann, S. The prevalence of chronic fatigue syndrome in Iceland - A national comparison by gender drawing on four different criteria. Nordic Journal of Psychiatry, 2002, 56, 4, 273-277.
The study was carried out to estimate the prevalence of CFS in Iceland. No previous prevalence studies known to us have been undertaken in Iceland or in Scandinavia. A 95-item custom-made questionnaire was sent to 4000 randomly selected people aged 19-75. The response rate was 63%. The questionnaire was constructed to include questions on all the items found in the four most common criteria for diagnosing CFS; the criteria being Australian [1988, Ed], British (Oxford) and American [CDC criteria 1988 and 1994].
Results show very different prevalences according to the criteria used. The prevalence ranged from 0 (Holmes et al 1988) to 4.9% (Australian), with the most established criteria yielding a prevalence of 1.4%. Re-test validity of the questionnaire was good, the following results are based on the selection criteria by Fukuda et al (n=54). Women were in a majority (78%); their mean age was 44, they were fully employed and worked long hours. They believed that the onset of their symptoms was stress related. The type of work was unskilled in the majority of cases. A significant proportion of the males felt a constant buzzing in their ears (p<0.05). Food suppliants were used daily by significantly more women than men (p<0.01). Men had more frequently phobic symptoms (p<0.001) than did women. Differences were found in the prevalence of phobia and panic (p<0.001) between women in the CFS group compared to healthy ones.
Brouwers, FM., Van Der Werf, S., Bleijenberg, G., Van Der Zee, L and Van Der Meer, JW. The effect of a polynutrient supplement on fatigue and physical activity of patients with chronic fatigue syndrome: a double-blind randomized controlled trial. Quarterly Journal of Medicine, 2002, 95, 10, 677-683.
Aim: To assess the effect of a polynutrient supplement on fatigue and physical activity of patients with CFS.
DESIGN: Prospective randomized placebo-controlled, double-blind trial.
METHODS: Fifty-three patients (16 males, 37 females) fulfilling the 1994 CDC criteria of CFS. The entry criteria were a score on the Checklist Individual Strength subscale fatigue severity (CIS fatigue) >/=40 and a weighted sum score of >/=750 for the eight subscales of the Sickness Impact Profile (SIP8) and no use of nutritional supplements in the 4 weeks prior to entry. The exclusion criteria were pregnancy and lactose intolerance.
The intervention - a polynutrient supplement containing several vitamins, minerals and (co)enzymes, or placebo, twice daily for 10 weeks - was preceded by 2 weeks of baseline measurements. Outcome measurements took place in week 9 and 10 of the intervention. Five participants dropped out (4 supplement, 1 placebo). The main outcome measures were CIS fatigue score, number of CDC symptoms and SIP8 score. Efficacy analyses were performed on an intention-to-treat basis.
RESULTS: No significant differences were found between the placebo and the treated group on any of the outcome measures: CIS fatigue (+2.16 p=0.984); CDC symptoms (+0.42 p=0.417); SIP8 +182 (p=0.297). No patient reported full recovery.
Smits, MG., van Rooy, R and Nagtegaal, JE. Influence of melatonin on quality of life in patients with chronic fatigue and late melatonin onset. Journal of Chronic Fatigue Syndrome, 2002, 10, (3/4), 25-36.
Medical Outcome Study Short Form-36 (MOS SF-36) qualities of life scores were studied in 38 chronic fatigue patients with late melatonin onset before and after treatment with melatonin. Before the start of the treatment, quality of life was assessed twice. Pre-treatment scores were compared with each other and with the scores of 43 patients with Delayed Sleep Phase Syndrome and of 1063 healthy subjects. Melatonin, 5 mg, was taken orally, 5 hours before baseline salivary endogenous dim light melatonin onset. Sleep architecture, measured at home, was normal. Melatonin was measured in saliva.
After mean (SD) treatment of 13.7 (0.8) weeks, quality of life scores of "physical functioning," "energy/vitality," "bodily pain," and "general health perception" improved (p values, respectively, 0.017, 0.002, 0.002 and 0.009). In the chronic fatigue patients the quality of life scores did not differ from those of the Delayed Sleep Phase Syndrome patients, except for "physical functioning," "energy/vitality" and "general health perception." These were significantly lower. All chronic fatigue patients' scores were significantly lower than those of the healthy subjects except for "health transition."
Chronic fatigue patients with late melatonin onset have a significant quality-of-life burden, similar to Delayed Sleep Phase Syndrome patients. Several quality of life dimensions improved after treatment with melatonin.
Patarca-Montero, R and Fletcher, MA. The Paul-Bunnell heterophile antibody determinant in Epstein-Barr virus-associated disease. Journal of Chronic Fatigue Syndrome, 2002, 10 (3/4), 51-86.
Reactivation of latent herpes viruses (notably Epstein-Barr virus, human herpesvirus-6) is commonly seen in CFS and it is believed to contribute to symptom perpetuation. Epstein-Barr virus (EBV), which was first isolated by Epstein, Barr and Achong (1964) from a cultured Burkitt's lymphoma lymphoblast cell line, is the etiological agent for infectious mononucleosis (IM), polyclonal and oligoclonal lymphomas associated with primary and acquired immunodeficiencies, and other disorders. The precise role of EBV in these diseases or in CFS is not well understood. Nonetheless, it is known that EBV infection triggers the formation of heterophile antibodies that, for many decades, have formed the basis for serologic diagnosis of IM. In this review, we discuss the discovery, species variation, and structure of the erythrocyte membrane-associated Paul-Bunnell (PB) heterophile antibody determinant, its implications to IM diagnosis, and its potential contribution to defective immune surveillance, such as that seen in CFS.
Bailly, L. Chronic fatigue syndrome or neurasthenia. British Journal of Psychiatry, 2002, 181, 350-351.
Letter based on inaccurate information (i.e. that ME is not listed in ICD-10) and asking what diagnosis these patients should be given. If neurasthenia is the same as ME, then what would the implications be for patients in need of treatment "for a psychiatric disorder'.
Brimacombe, M., Zhang, Q., Lange, G and Natelson, BH. Immunological variables mediate cognitive dysfunction in Gulf war veterans but not civilians with chronic fatigue syndrome. Neuroimmunomodulation, 2002, 10, 2, 93-100.
We explored the relationship between a set of immunological variables and a set of cognitive and functional status measures and a diagnosis of CFS in civilians and veterans using various regression and factor analytic methods.
Our approach emphasized the extraction of a few distinct factors in order to limit statistical problems associated with doing large numbers of multiple comparisons. This approach led to our finding cytokine data grouping into type 1 and type 2 clusters. A type 2 cluster plus a T and B cell factor predicted CFS caseness for Gulf War veterans but not for civilians with CFS. When a cognitive variable, reaction time, was added into the model, both immunological factors lost statistical significance; this indicates that the cognitive variable reaction time moderated the effects of the immunological factors in predicting patient status.
We did a similar analysis on the roles of the immunological and cognitive variables in functional status using SF-36 data. Higher levels of these same two immunological factors predicted poorer general health as well as poorer physical and social functioning in Gulf War veterans but not in civilians with CFS. When the reaction time factor was added, only the lymphocyte factor remained significant. This implies that lymphocytes are directly related to functional status in Gulf War veterans with CFS, but the Th2 factor produces its effect on functional status via changes in cognitive abilities.
Demettre, E., Bastide, L., D'Haese, A., De Smet, K., De Meirleir, K., Tiev, KP., Englebienne, P and Lebleu, B. Ribonuclease L proteolysis in peripheral blood mononuclear cells of chronic fatigue syndrome patients. Journal of Biological Chemistry, 2002, 277, 38, 35746-35751.
Abstract, see September issue.
Goudsmit, EM. Chronic fatigue syndrome. British Journal of General Practice, 2002, 52, 12, 1023-1024
Reply to Stanley et al's defamatory comment regarding the respondent's ability to read and interpret scientific publications.
Lerner, AM., Beqaj, SH., Deeter, RG et al. A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs Today, 2002, 38, 8, 549-561.
Naschitz, JE., Sabo, E., Naschitz, S., Rosner, I., Rozenbaum, M., Priselac, RM., Gaitini, L., Zukerman, E and Yeshurun, D. Fractal analysis and recurrence quantification analysis of heart rate and pulse transit time for diagnosing chronic fatigue syndrome. Clinical Autonomic Research, 2002, 12, 4, 264-272.
This study aimed to develop a method to distinguish between the cardiovascular reactivity in CFS and other patient populations.
Patients with CFS (n=23), familial Mediterranean fever (n=15), psoriatic arthritis (n=10), generalized anxiety disorder (n=12), neurally mediated syncope (n=20), and healthy subjects (n=20) were evaluated with a shortened head-up tilt test (HUTT). A 10-minute supine phase of the HUTT was followed by recording 600 cardiac cycles on tilt, i.e., 5 to 10 minutes. Beat-to-beat heart rate (HR) and pulse transit time (PTT) were acquisitioned. Data were processed by recurrence plot and fractal analysis. Fifty-two variables were calculated in each subject.
On multivariate analysis, the best predictors of CFS were HR-tilt-R/L, PTT-tilt-R/L, HR-supine-DET, PTT-tilt-WAVE, and HR-tilt-SD. Based on these predictors, the 'Fractal & Recurrence Analysis-based Score' (FRAS) was calculated: FRAS = 76.2 +0.04* HR-supine-DET -12.9*HR-tilt-R/L -0.31*HR-tilt-SD -19.27* PTT-tilt-R/L -9.42* PTT-tilt-WAVE. The best cut-off differentiating CFS from the control population was FRAS= +0.22. FRAS >+ 0.22 was associated with CFS (sensitivity 70% and specificity 88%). The cardiovascular reactivity received mathematical expression with the aid of the FRAS. The shortened HUTT was well tolerated. The FRAS provides objective criteria which could become valuable in the assessment of CFS.
Natelson, BH. A status report on chronic fatigue syndrome. Environmental Health Perspectives, 2002, 110 Suppl 4, 673-677.
Medical history has shown that clinical disease entities or syndromes are composed of many subgroups - each with its own cause and pathogenesis. Although we cannot be sure, we expect the same outcome for CFS, a medically unexplained condition characterized by disabling fatigue accompanied by infectious, rheumatological, and neuropsychiatric symptoms.
Although the ailment clearly can occur after severe infection, no convincing data exist to support an infectious (or immunologic) process in disease maintenance. Instead, data point to several possible pathophysiological processes: a covert encephalopathy, impaired physiological capability to respond to physical and mental stressors, and psychological factors related to concerns about effort exacerbating symptoms.
Each of these is under intense investigation. In addition, some data do exist to indicate that environmental agents also can elicit a state of chronic fatigue. We expect data to accumulate to support the belief that CFS has multiple causes.
Nijs, J., Vaes, P., Van Hoof, E., De Becker, P, McGregor, N and De Meirleir, K. Activity limitations and participation restrictions in patients with chronic fatigue syndrome - construction of a disease specific questionnaire. Journal of Chronic Fatigue Syndrome, 2002, 10, (3/4), 3-23.
Review of the literature indicated the lack of disease specific measures for assessing activity limitations and participation restriction in patients with CFS. Retrospective analysis of Karnofsky Performance Status questionnaires and Activities of Daily Living questionnaires (a Dutch version of the Barthel index, modified for CFS) of 141 subjects was performed to create a new questionnaire. Definition of CFS used: CDC 1994.
Data analysis resulted in the following item selection, based on most frequently reported activity limitations and participation restriction; cleaning, washing dishes and returning them to cupboard, iron, do the wash, gardening, replace light bulb, walking, climb one flight of stairs, stand one hour, sit two hours, doing groceries, thirty minutes of computer work, carrying heavy objects, write a full page letter, use a screwdriver, hammer a nail, make one bed, reading, social activities, doing sports, studying, driving a car, going to school/working, preparing meals and caring for a child. These data were used to create the CFS-Activities and Participation Questionnaire (CFS-APQ). The reliability and different aspects of validity of this new measure still need to be established.
Nijs, J., Nicolson, GL., De Becker, P., Coomans, D and De Meirleir, K. High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients. FEMS Immunology & Medical Microbiology, 2002, 34, 209-214.
Prevalence of Mycoplasma species infections in CFS has been extensively reported in the scientific literature. However, all previous reports highlighted the presence of Mycoplasmas in American patients. In this prospective study, the presence of Mycoplasma fermentans, M. penetrans, M. pneumoniae and M. hominis in the blood of 261 European CFS patients and 36 healthy volunteers was examined using forensic polymerase chain reaction.
One hundred and seventy-nine (68.6%) patients were infected by at least one species of Mycoplasma, compared to two out of 36 (5.6%) in the control sample (p<0.001). Among Mycoplasma-infected patients, M. hominis was the most frequently observed infection (n=96; 36.8% of the overall sample), followed by M. pneumoniae and M. fermentans infections (equal frequencies; n=67; 25.7%). M. penetrans infections were not found. Multiple mycoplasmal infections were detected in 45 patients (17.2%).
Compared to American CFS patients (M. pneumoniae>M. hominis>M. penetrans), a slightly different pattern of mycoplasmal infections was found in European CFS patients (M. hominis>M. pneumoniae, M. fermentans> M. penetrans).
Raine, R., Haines, A., Sensky, T., Hutchings, A., Larkin, K and Black N. Systematic review of mental health interventions for patients with common somatic symptoms: can research evidence from secondary care be extrapolated to primary care? BMJ, 2002, 325, (7372), 1082-1085.
Systematic review to determine the strength of evidence for the effectiveness of mental health interventions for patients with three common somatic conditions (CFS, irritable bowel syndrome, and chronic back pain). To assess whether results obtained in secondary care can be extrapolated to primary care and suggest how future trials should be designed to provide more rigorous evidence.
Results: For some interventions, such as brief psychodynamic interpersonal therapy, little research was identified. However, results of meta-analyses and of randomised controlled trials suggest that CBT and behaviour therapy are effective for chronic back pain and CFS and that antidepressants are effective for irritable bowel syndrome. CBT and behaviour therapy were effective in both primary and secondary care in patients with back pain, although the evidence is more consistent and the effect size larger for secondary care. Antidepressants seem effective in irritable bowel syndrome in both settings but ineffective in CFS.
Conclusions: Treatment seems to be more effective in patients in secondary care than in primary care. This may be because secondary care patients have more severe disease, they receive a different treatment regimen, or the intervention is more closely supervised. However, conclusions of effectiveness should be considered in the light of the methodological weaknesses of the studies. Large pragmatic trials are needed of interventions delivered in primary care by appropriately trained primary care staff.
Stanley, IM., Peters, S and Salmon, P. A primary care perspective on prevailing assumptions about persistent medically unexplained physical symptoms. International Journal of Psychiatry in Medicine, 2002, 32, 2, 125-140.
Objective: To re-examine the widespread assumption that medically unexplained physical symptoms represent discrete syndromes resulting from somatization of mental illness.
Method: Primary care patients (N=223) with medically unexplained symptoms of at least one year's duration were recruited to a study of exercise therapy. Data gathered from patients, from their general practitioners, and from medical records were used to examine relationships between self-defined disability, symptoms, mental state, and use of health care.
Results: Levels of disability and health care use were both raised, but were only weakly correlated. While most patients were depressed and/or anxious, a minority (14 percent) were neither. Although mental state correlated with disability, health care use was unrelated to either. Among a wide range of recorded symptoms, few correlations were found to support the existence of discrete syndromes. Analysis of agreement between patients and their doctors in assigning symptoms to broadly defined "syndromes" appears to reflect collaboration that is largely expedient.
Conclusions: In this sample of primary care patients with persistent unexplained physical symptoms, we found little evidence of discrete somatic syndromes.
Van der Werf, SP, de Vree, B., Alberts, M, van der Meer, JWM and Bleijenberg, G. Natural course and predicting self-reported improvement in patients with chronic fatigue syndrome with a relatively short illness duration. Journal of Psychosomatic Research, 2002, 53, 3, 749-753.
Objective: To describe the course of fatigue in patients with CFS and ICF (idiopathic chronic fatigue).
Methods: Seventy-nine patients with CFS of less than 2 years were tested at baseline and 78 of the same group at 1-year follow-up. During this time period, no systematic intervention took place. Self-reported improvement and fatigue severity were the main outcome measures.
Results: Forty-six percent of the patients with a short illness duration reported to be improved. This was a significantly (p<.001) higher percentage compared to the 20% self-reported improvement in a previously published natural-course study among 246 CFS patients with a longer illness duration.
Persistence of complaints after 1-year follow-up was associated with high baseline levels of experienced concentration problems, less strong psychosocial causal explanations for the complaints, and higher levels of the experienced lack of social support. Baseline fatigue severity predicted fatigue severity at follow-up. No group differences were found for psychological distress, causal attributions (physical), activity ratings and self-efficacy.
Conclusion: The results showed that CFS patients with a relatively short duration of complaints had a more favourable outcome compared to patients with a long illness duration. The data also indicated that complete recovery only occurred in patients with a complaint duration of less than 15 months. This finding has important implications, since it suggests that after such a time period spontaneous recovery hardly occurs.
Van Hoof, E., Coomans, D., Cluydts R, et al. Correlation of immunologic parameters to psychological variables in chronic fatigue syndrome. International Journal of Psychophysiology, 2002, 45, (1-2), 71-71.
Van Hoof, E., Coomans, D., De Becker, R, et al. Hyperbaric oxygen therapy for chronic systemic infections in chronic fatigue syndrome. International Journal of Psychophysiology, 2002, 45, (1-2), 82-83.
Van Hoof, E., Coomans, D., Cluydts R, et al. Correlation of sleep parameters to immunological variables in chronic fatigue syndrome. International Journal of Psychophysiology, 2002, 45, (1-2): 169-169.
Various. Letters. British Journal of General Practice, 2002, 52, 762-764.
Letters responding to the editorial by Stanley et al (ibid, 355-356) by Pall, M., Sykes, R and Goudsmit, EM. With reply by the authors.
White, PD., Pinching, AJ., Rakib, A., Castle, M., Hedge, B and Priebe, S. A comparison of patients with chronic fatigue syndrome attending separate fatigue clinics based in immunology and psychiatry. Journal of the Royal Society of Medicine, 2002, 95, 9, 440-444.
Hospital clinics for patients with chronic unexplained fatigue are held in departments of various disciplines. This causes difficulties for referrers in choosing the appropriate clinic and for researchers in generalizing findings from one type of clinic to others. We randomly selected 37 outpatients attending an immunology fatigue clinic and 36 outpatients attending a psychiatry fatigue clinic, all of whom had CFS (Oxford definition). We compared demographic factors, symptoms, disability, quality of life, psychological distress and illness attributions.
The patients from the two clinics were closely similar in their specific symptoms, disability, quality of life, psychological distress and previous attendance to mental health professionals. Psychological distress was high and equal in the two samples. The proportion of men was greater among patients attending the immunology clinic. In a post-hoc analysis, 64% of immunology attenders attributed their fatigue to physical factors, compared with 31% of psychiatry clinic attenders (p=0.01).
These findings suggest that research data from one type of chronic fatigue clinic can be generalized to others. Clinically similar patients are referred to different clinics, and the choice of clinic may be influenced by the patients' illness beliefs. The high levels of emotional distress suggest that psychosocial management is as important as physical management in hospital outpatients with CFS, irrespective of its aetiology.
White, PD. Chronic unexplained fatigue. Postgraduate Medical Journal, 2002, 78, 445-446.
Editorial commenting on the Report for the CMO.
White, PD and Fulcher, FY. Chronic fatigue syndrome, deconditioning, and graded exercise therapy. Medicine & Science in Sports and Exercise, 2002, 34, 10, 1691-1693.
Letter responding to Sargent et al (ibid, 2002, 34, 1, 56). With reply by Sargent and Scroop, noting the difference between 'exercise capacity' and 'exercise performance'. The latter is generally impaired but the 'metabolic engine' of CFS patients was no different from that expected in healthy, sedentary individuals of similar age and gender. Thus the study in question found no evidence of a reduction in exercise capacity and therefore no physiological basis for instituting an exercise-training programme.
Zachrisson, O., Regland, B., Jahreskog, M., Jonsson, M., Kron, M and Gottfries, CG. Treatment with staphylococcus toxoid in fibromyalgia/chronic fatigue syndrome-a randomised controlled trial. European Journal of Pain, 2002, 6, 6, 455-466.
We have previously conducted a small treatment study on staphylococcus toxoid in fibromyalgia (FM) and CFS. The aim of the present study was to further assess the efficacy of the staphylococcus toxoid preparation Staphypan Berna (SB) during 6 months in FM/CFS patients.
One hundred consecutively referred patients fulfilling the ACR criteria for FM and the 1994 CDC criteria for CFS were randomised to receive active drug or placebo. Treatment included weekly injections containing 0.1ml, 0.2ml, 0.3ml, 0.4ml, 0.6ml, 0.8ml, 0.9ml, and 1.0ml SB or coloured sterile water, followed by booster doses given 4-weekly until endpoint. Main outcome measures were the proportion of responders according to global ratings and the proportion of patients with a symptom reduction of >/=50% on a 15-item subscale derived from the comprehensive psychopathological rating scale (CPRS).
The treatment was well tolerated. Intention-to-treat analysis revealed 32/49 (65%) responders in the SB group compared to 9/49 (18%) in the placebo group (p<0.001). Sixteen patients (33%) in the SB group reduced their CPRS scores by at least 50% compared to five patients (10%) in the placebo group (p<0.01). Mean change score on the CPRS (95% confidence interval) was 10.0 (6.7-13.3) in the SB group and 3.9 (1.1-6.6) in the placebo group (p<0.01). An increase in CPRS symptoms at withdrawal was noted in the SB group.
In conclusion, treatment with staphylococcus toxoid injections over 6 months led to significant improvement in patients with FM and CFS. Maintenance treatment is required to prevent relapse.
Miller, RG. Role of fatigue in limiting physical activities in humans with neuromuscular diseases. American Journal of Physical Medicine & Rehabilitation, 2002, 81, 11, S99-S107.
New methods of examining both central and peripheral fatigue are now available. A broader understanding of the mechanisms of fatigue in healthy human subjects has begun to emerge.
The mechanisms of fatigue in patients with various neuromuscular diseases are even more complex than in healthy persons. Examples of both central and peripheral fatigue in various neuromuscular diseases and other disorders are presented, including metabolic myopathy, CFS, postpolio syndrome, and amyotrophic lateral sclerosis.
Pall, ML. NMDA sensitization and stimulation by peroxynitrite, nitric oxide, and organic solvents as the mechanism of chemical sensitivity in multiple chemical sensitivity. The FASEB Journal, 2002, 16, 1407-1417.
Multiple chemical sensitivity (MCS) is a condition where previous exposure to hydrophobic organic solvents or pesticides appears to render people hypersensitive to a wide range of chemicals, including organic solvents. The hypersensitivity is often exquisite, with MCS individuals showing sensitivity that appears to be at least two orders of magnitude greater than that of normal individuals. This paper presents a plausible set of interacting mechanisms to explain such heightened sensitivity. It is based on two earlier theories of MCS: the elevated nitric oxide/peroxynitrite theory and the neural sensitization theory. It is also based on evidence implicating excessive NMDA activity in MCS. Four sensitization mechanisms are proposed to act synergistically, each based on known physiological mechanisms: Nitric oxide-mediated stimulation of neurotransmitter (glutamate) release; peroxynitrite-mediated ATP depletion and consequent hypersensitivity of NMDA receptors; peroxynitrite-mediated increased permeability of the blood-brain barrier, producing increased accessibility of organic chemicals to the central nervous system; and nitric oxide inhibition of cytochrome P450 metabolism. Evidence for each of these mechanisms, which may also be involved in Parkinson's disease, is reviewed. These interacting mechanisms provide explanations for diverse aspects of MCS and a framework for hypothesis-driven MCS research.
Schwartz, PY. Why is neurasthenia important in Asian cultures? Western Journal of Medicine, 2002, 176, 257-258.
Discussion of neurasthenia including acknowledgement of the similarity between the definitions of the former and CFS.
Brostoff, J and Challacombe, SJ. Food Allergy and Intolerance. London: Saunders: 2002. 977pp. Hb. £145.
Second edition of this respected textbook. Includes chapter by Goudsmit, EM on the psychologisation of illnesses, including ME (p. 685-693.)
Fitzgibbon, J. Feeling tired all the time. Dublin: Newleaf. 2002. 396 pp. Pb. £13.40.
Sympathetic self-help guide focusing on the main causes of fatigue, including depression, stress, nutritional deficiencies, MCS and CFS. The section on CFS approaches the condition largely from a cognitive-behavioural perspective and does not recognise ME as a subgroup.
Rotholz, JM. Chronic fatigue syndrome, christianity, & culture. NY: Haworth Press. 141 pp. Pb. $14.36 plus $5 outside US. (www.HaworthPress.com)
Personal account of the illness and thoughts on our cultural values by a Christian anthropologist who developed CFIDS while working as a lecturer. Thought-provoking, though some may not agree with all the author's theological interpretations.
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