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Kerr, JR., Cunniffe, VS., Kelleher, P., Bernstein, RM and Bruce, IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome. Clinical Infectious Diseases, 2003, 36, 9, E100-106.
Three cases of CFS that followed acute parvovirus B19 infection were treated with a 5-day course of intravenous immunoglobulin (IVIG; 400 mg/kg per day), the only specific treatment for parvovirus B19 infection. We examined the influence of IVIG treatment on the production of cytokines and chemokines in individuals with CFS due to parvovirus B19. IVIG therapy led to clearance of parvovirus B19 viremia, resolution of symptoms, and improvement in physical and functional ability in all patients, as well as resolution of cytokine dysregulation.
Nijs, J., De Becker, P., De Meirleir, K., Demanet, C., Vincken, W., Schuermans, D and McGregor, N. Associations between bronchial hyperresponsiveness and immune cell parameters in patients with chronic fatigue syndrome. Chest, 2003, 123, 4, 998-1007.
Tiev, KP., Demettre, E., Ercolano, P., Bastide, L., Lebleu, B and Cabane, J. RNase L levels in peripheral blood mononuclear cells: 37-Kilodalton/83-Kilodalton isoform ratio is a potential test for chronic fatigue syndrome. Clinical and Diagnostic Laboratory Immunology, 2003, 10, 2, 315-316.
CFS is a disorder characterized by debilitating fatigue associated with immunological abnormalities. The etiology remains unclear. A low-molecular-mass (37 kDa) isoform of RNase L has been described in peripheral blood mononuclear cell (PBMC) extracts, and the ratio of two isoforms of RNase L (37 kDa/83 kDa) has been proposed as a potential biochemical marker of CFS.
In a prospective case-control study, we tested whether the RNase L 37-kDa/83-kDa ratio could discriminate a CFS population. We compared the ratio of RNase L isoforms in PBMCs from 11 patients with CFS (CDC criteria '94, no infectious history in previous month, 6 women and 5 men; mean age 43.2 years, no infection in previous month) and PBMCs from 14 healthy well-matched volunteers (10 women and 4 men; age, 39.1 years).
A ratio of RNase L of 0.4 used as a threshold allowed diagnosis of CFS with high sensitivity (91%; 95% confidence interval [CI], 57 to 99%) and specificity (71%; 95% CI, 41 to 90%). The positive and negative prognostic values were 71% (95% CI, 41 to 90%) and 91% (95% CI, 57 to 99%), respectively.
In the absence of acute infection or chronic inflammation, a high RNase L ratio could distinguish CFS patients from healthy volunteers. Additional large studies and follow-up studies are required to confirm the stability of this high ratio of RNase L isoforms in a CFS group. In CFS, the accumulation of fragments with a molecular mass of 37 kDa could be due to an increased protolytic activity in PBMC extracts.
Chaudhuri, A., Condon, BR., Gow, JW., Brennan, D and Hadley, DM. Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome. Neuroreport, 2003, 14, 2, 225-228.
Fatigue is a common symptom of neurological diseases that affect basal ganglia function. We used proton magnetic resonance spectroscopy (1H MRS) to study the metabolic functions of the basal ganglia in CFS to test the hypothesis that fatigue in CFS may have a neurogenic component.
1H MRS of left basal ganglia was carried out in 8 non-psychiatric patients with CFS (CDC criteria '94, no evidence of ongoing systemic infection or clinical depression) and their results were compared to age- and sex-matched healthy asymptomatic healthy controls.
A highly significant increase in the spectra from choline-containing compounds was seen in the CFS patient group (p<0.001). There was no evidence for a loss of neuronal mass in the basal ganglia. In the absence of regional structural or inflammatory pathology, increased choline resonance in CFS may be an indicator of higher cell membrane turnover due to gliosis or altered intramembrane signalling. The results suggest local changes in neural cell membrane lipid composition rather than a systemic disorder of lipid metabolism.
Cook, DB., Nagelkirk, PR. Peckman, A., Poluri, A., LaManca, JJ and Natelson, BH. Perceived exertion in fatiguing illness: civilians with chronic fatigue syndrome. Medicine & Science in Sports and Exercise, 2003, 35, 4, 563-568.
It has been reported that ratings of perceived exertion (RPE) are elevated in CFS. However, methodological limitations have rendered this conclusion suspect. The purpose of the present investigation was to examine RPE during exercise in civilians with CFS by comparing subjects at both absolute exercise stage and relative oxygen consumption reference criteria.
A sample of 39 civilian females, 19 with CFS (CDC criteria '88 and '94) and 20 healthy, sedentary controls underwent a maximal exercise test on a treadmill. RPE were obtained during the last 15s of each 3-min stage using Borg's 6-20 scale.
There were no significant differences in peak VO2, RER (respiratory exchange ratio), or RPE. However, controls exercised longer (20.0 vs 15.9 min, p=0.01, healthy vs CFS) and had higher peak HR (183 vs 174 bpm, p=0.03, healthy vs CFS). Civilians with CFS reported higher RPE at stages 3 through 5 compared with controls (p=0.017). Pre-exercise fatigue ratings were not a significant predictor of perceived exertion during exercise. There were no group differences (p=0.17) when RPE were expressed relative to peak VO2.
Our results show that RPE are greater in civilians with CFS when the data are expressed in terms of absolute exercise intensity. However, by examining RPE relative to a common maximum (i.e., peak VO2) no differences were observed. The findings of the present investigation challenge the notion that RPE are dysregulated in CFS. Thus alterations in effort sense probably do not result in exacerbated feelings of fatigue.
See also Cook et al, ibid, 569-574 reporting different results in Gulf War veterans with CFS.
Gaab, J., Huster, D., Peisen, R., Engert, V., Heitz, V., Schad, T., Schurmeyer, T and Ehlert, U. Assessment of cortisol response with low-dose and high-dose ACTH in patients with chronic fatigue syndrome and healthy comparison subjects. Psychosomatics, 2003, 44, 2, 113-119.
A reduced secretion of cortisol has been proposed as a possible explanation of the symptoms in CFS. However, the evidence of hypocortisolism in CFS is conflicting. In order to simultaneously assess possible alterations in adrenocortical sensitivity and secretory adrenal reserve, the authors administered both low-dose and high-dose ACTH to a group of 18 CFS patients and 18 age- and gender-matched healthy comparison subjects.
No response differences for salivary and plasma cortisol were detectable after administration of either low-dose or high-dose ACTH, indicating that primary adrenal insufficiency is unlikely to play a significant role in the etiology of CFS.
Georgiades, E., Behan, WM., Kilduff, LP., Hadjicharalambous, M., Mackie, EE., Wilson, J., Ward, SA and Pitsiladis, YP. Chronic fatigue syndrome: new evidence for a central fatigue disorder. Clinical Science (Lond), 2003, 23rd April; [epub ahead of print].
Considerable evidence points towards a prominent role for central neural (CNS) mechanisms in the pathogenesis of CFS. We wished to characterise circulating profiles of putative amino acid modulators of CNS serotoninergic and dopaminergic function in CFS patients at rest, during symptom-limited exercise and subsequent recovery.
Twelve CFS patients and eleven age- and sex-matched sedentary controls, with similar physical activity histories, underwent ramp-incremental exercise to the limit of tolerance. Plasma amino acid concentrations, oxygen uptake (VO2) and ratings of perceived exertion (RPE) were measured at rest, during exercise and recovery.
Peak oxygen uptake (VO2 peak) was significantly lower in the CFS patients, compared to controls. RPE in the patients was higher at all measured time points, including rest, relative to controls. Levels of free tryptophan [free Trp], the rate-limiting serotoninergic precursor, were significantly higher in CFS patients at exhaustion and recovery, whereas concentrations of branched-chain and large-neutral amino acids (BCAA and LNAA, respectively) were lower in patients at exhaustion and, for [LNAA], also during recovery. Consequently, the [free Trp]:[BCAA] and [free Trp]:[LNAA] ratios were significantly higher in CFS patients, except at rest. On the other hand, levels of tyrosine, the rate-limiting dopaminergic precursor, were significantly lower at all time points in the patients.
The significant differences observed in a number of key putative CNS serotoninergic and dopaminergic modulators, coupled with the exacerbated effort perception, provide further evidence for a potentially significant role of CNS mechanisms in CFS pathogenesis.
McCully, KK., Smith, S., Rajaei, S., Leigh Jr, JS and Natelson, BH. Blood flow and muscle metabolism in chronic fatigue syndrome. Clinical Science, (Lond), 2003, Feb 18; [epub ahead of print].
The purpose of this study was to determine if CFS is associated with reduced blood flow and oxidative delivery to skeletal muscle.
Patients with CFS according to CDC criteria (n=19) were compared to normal sedentary subjects (n=11). Muscle blood flow was measured with Doppler ultrasound after cuff ischemia and after exercise. Muscle oxygen delivery was measured as the rate of post-exercise and post-ischemic oxygen-heme resaturation. Oxygen-heme resaturation was measured in the medial gastrocnemius muscle using continuous wavelength near-infrared spectroscopy. Muscle metabolism was measured using 31P magnetic resonance spectroscopy.
CFS and controls were not different in the peak blood flow after cuff ischemia, the rate of recovery of phosphocreatine after submaximal exercise, and the rate of recovery of oxygen saturation after cuff ischemia. Thus, CFS patients showed no deficit in blood flow or oxidative metabolism. This suggests that CFS symptoms do not require abnormal peripheral function.
Naschitz, JE., Itzhak, R., Shaviv, N., Khorshidi, I., Sundick, S., Isseroff, H., Fields, M., Priselac, RM., Yeshurun, D and Sabo, E. Assessment of cardiovascular reactivity by fractal and recurrence quantification analysis of heart rate and pulse transit time. Journal of Human Hypertension, 2003, 17, 111-118.
Methods used for the assessment of cardiovascular reactivity are flawed by nonlinear dynamics of the cardiovascular responses to stimuli. In an attempt to address this issue, we utilized a short postural challenge, recorded beat-to-beat heart rate (HR) and pulse transit time (PTT), assessed the data by fractal and recurrence quantification analysis, and processed the obtained variables by multivariate statistics.
A 10-min supine phase of the head-up tilt test was followed by recording 600 cardiac cycles on tilt, that is, 5-10 min. Three groups of patients were studied, each including 20 subjects matched for age and gender - healthy subjects, patients with essential hypertension (HT), and patients with CFS (CDC criteria 1994). The latter group was studied on account of the well-known dysautonomia of CFS patients, which served as contrast against the cardiovascular reactivity of the healthy population.
A total of 52 variables of the HR and PTT were determined in each subject. The multivariate model identified the best predictors for the assessment of reactivity of healthy subjects vs CFS. Based on these predictors, the 'Fractal & Recurrence Analysis-based Score' (FRAS) was calculated: FRAS=76.2+0.04*HR-supine-DET -12.9*HRtilt-R/L -0.31*HR-tilt-s.d. -19.27*PTT-tilt-R/L -9.42*PTT-tilt-WAVE. The median values and IQR of FRAS in the groups were: healthy=-1.85 (IQR 1.89), hypertensives=+0.52 (IQR 5.78), and CFS=-24.2 (5.34) (HT vs healthy subjects: p=0.0036; HT vs CFS: p<0.0001).
Since the FRAS differed significantly between the three groups, it appears likely that the FRAS may recognize phenotypes of cardio-vascular reactivity.
Razumovsky, AY., DeBusk, K., Calkins, H., Snader, S., Lucas, KE., Vyas, P., Hanley, DF and Rowe, PC. Cerebral and systemic hemodynamics changes during upright tilt in chronic fatigue syndrome. Journal of Neuroimaging, 2003, 13, 1, 57-67.
During head-up tilt (HUT), patients with CFS have higher rates of neurally mediated hypotension (NMH) and postural tachycardia syndrome (POTS) than healthy controls. The authors studied whether patients with CFS were also more likely to have abnormal cerebral blood flow velocity (CBFV) compared with controls in response to orthostatic stress.
Transcranial Doppler monitoring of middle cerebral artery (MCA) CBFV was performed during 3-stage HUT prospectively in 26 patients with CFS and 23 healthy controls. At the same time, continuous monitoring of arterial blood pressure (BP), heart rate (HR), endtidal CO2 (ET-CO2) were performed. Results are reported as mean +/- SD.
NMH developed in 21 patients with CFS and in 14 controls (p=.22). POTS was present in 9 CFS patients and 7 controls (p=.76). Supine HR was higher in CFS patients, but all other hemodynamics and CBFV measures were similar at baseline. The median time to hypotension did not differ, but the median time to onset of orthostatic symptoms was shorter in those with CFS (p<.001). The CBFV did not differ between groups in the supine posture, at 1 or 5 minutes after upright tilt, at 5 or 1 minute before the end of the test, or at termination of the test. Mean CBFV fell at termination of tilt testing in those with CFS and controls. ET-CO2 was lower at termination of the test in those with CFS versus controls (p=.002).
The results of this study are not consistent with the hypothesis that patients with CFS have a distinctive pattern of MCA CBFV changes in response to orthostatic stress.
Racciatti, D., Guagnano, MT., Vecchiet, J., De Remigis, PL., Pizzigallo, E., Della Vecchia, R., Di Sciascio, T., Merlitti, D and Sensi S. Chronic fatigue syndrome: circadian rhythm and hypothalamic-pituitary-adrenal (HPA) axis impairment. International Journal of Immunopathology and Pharmacology 2001, 14, 1, 11-15.
The aim of our study was to evaluate possible alterations of the hypothalamic-pituitary-adrenal (HPA) axis in our CFS patients by studying the circadian rhythms of prolactin (PRL), thyrotropic hormone (TSH), adrenocorticotropic hormone (ACTH), and cortisol (CS).
A total of 36 patients were enrolled according to the CDC criteria. Twenty healthy subjects were included as controls. Blood samples were taken every 4 hours during a single 24-hour period. We performed a fluorometric enzyme immunoassay with serum PRL, cortisol and TSH, and an immunoradiometric assay with plasma ACTH.
The circadian rhythms of PRL, TSH, ACTH and CS were statistically significant in both CFS and control groups. At 24:00 and 04:00 hrs the CFS patients showed lower ACTH levels than healthy subjects (p<0.001); the PRL levels were higher at 04.00 h in CFS patients than in healthy subjects.
Ciccone, DS., Busichio, K., Vickroy, M and Natelson, BH. Psychiatric morbidity in the chronic fatigue syndrome: Are patients with personality disorder more physically impaired? Journal of Psychosomatic Research, 2003, 54, 445-452.
The long-term consequences of CFS include substantial impairment in physical functioning and high levels of work disability... some have speculated that it may be due to comorbid psychiatric illness or personality disorder. We addressed this possibility by comparing the functional status of three CFS groups: no psychiatric diagnosis, psychiatric illness only, psychiatric illness and personality disorder. A second aim of the study was to determine whether a continuous measure of psychological distress could provide a better account of impairment than psychiatric diagnosis.
The study sample consisted of 84 consecutive female referrals with CFS (CDC criteria '94). All participants completed an assessment protocol consisting of: physical examination, psychiatric interview (DIS) and self-report questionnaires.
There was a high rate of psychiatric disorder (about half having a lifetime history of psychiatric illness. Of these, 44% met criteria for one or more personality disorder. Personality disorders were also found in some without a history of psychiatric illness (33%). There was no association between psychiatric disorder and either physical functioning or disability. A regression model of physical functioning found that psychological distress accounted for 6% and symptom severity for 41% of the variance (p=.06 and <.01, respectively). In the case of disability, the corresponding percentages were 2% and 18% (NS and p<.01, respectively). The modest effects of psychological distress could not be attributed to symptom severity. Core symptoms of CFS, fatigue and pain, were more successful in accounting for physical functioning (41%, 34% after controlling for distress) and physical disability (18%). Fatigue was more important in performing physical activities than pain.
Although psychiatric illness and personality disorder were prevalent (in this sample), neither could explain the effects of CFS on physical functioning and disability...
Ciccone, DS and Natelson, BH. Comorbid illness in women with chronic fatigue syndrome: a test of the single syndrome hypothesis. Psychosomatic Medicine, 2003, 65, 2, 268-275.
Evidence of comorbidity among unexplained illness syndromes raises the possibility that all are variants of a single functional disorder, leading some to suggest that separate case definitions for CFS, fibromyalgia (FM), and multiple chemical sensitivity (MCS) may be unnecessary. Our objective was to determine whether discrete diagnostic labels provide useful information about physical functioning, symptom severity, and risk of psychiatric illness.
The sample consisted of 163 consecutive female referrals with CFS (CDC criteria '94) enrolled at a tertiary clinic. Each participant was retrospectively assigned to one of four groups: CFS only, CFS/FM, CFS/MCS, and CFS/FM/MCS. At enrollment, participants gave their history, underwent a physical examination and a psychiatric interview (DIS), and answered self-report questionnaires.
Additional unexplained syndromes were prevalent: 37% met criteria for FM, and 33% met criteria for MCS. With the exception of FM-related pain and disability, there were few differences between the CFS only (n=62, 38% of the total) and CFS with comorbid illness groups. Patients with additional illness were more likely to have major depression and a higher risk of psychiatric morbidity compared with patients in the CFS only group (p<.01). Rates of life-time depression increased from 27.4% in the CFS only group to 52.3% in the CFS/FM group, 45.2% in the CFS/MCS group, and 69.2% in the CFS/FM/MCS group.
The prevalence of comorbid illness in the present CFS sample and the failure to find widespread differences in symptom severity can be seen as support for the single syndrome hypothesis. On the other hand, the existence of discrete syndromes could not be ruled out because of reliable differences between CFS and CFS/FM (e.g risk of generalized anxiety disorder). Increasing comorbidity was associated with a corresponding increase in risk of major depression.
Creswell, C and Chalder, T. The relationship between illness attributions and attributional style in chronic fatigue syndrome. British Journal of Clinical Psychology, 2003, 42 (Pt 1): 101-104
Jason, LA., Witter, E and Torres-Harding, S. Chronic fatigue syndrome, coping, optimism and social support. Journal of Mental Health, 2003, 12, 2, 109-118.
Prior studies indicate that problem-focused coping, a realistic optimistic explanatory style, and appropriate social support appear to be related to positive health outcomes and greater well-being. It was hypothesized that coping styles, optimism, amount of social support and quality of social support would significantly differ among those with CFS (CDC criteria '94), idiopathic chronic fatigue, chronic fatigue resulting from a medical condition, and a control group.
Participants in the idiopathic chronic fatigue group had the lowest optimism scores and satisfaction with their social supports. Those in the medically explained condition used significantly more venting and focusing on symptoms than controls. The CFS group had higher levels of optimism and satisfaction with social supports than the other two chronically fatigued groups, and behavioral disengagement was related to worse mental composite scores (MOS), while maintaining activities and optimism was related to more positive mental composite scores. Thus psychological factors, such as coping styles, optimism, and perceived social support are correlated with mental and physical health outcomes...
[Ed. note: The CFS group did not have higher scores than the controls or medically explained fatigue group for focusing on symptoms. This is significant given the speculation about introspection. There were also similar scores for maintaining activity. As a group, the scores for behavioural disengagement were lower than those of the medically explained fatigue group. Thus there is little evidence for significant 'avoidance'.]
Rangel L, Garralda ME, Hall A, Woodham S. Psychiatric adjustment in chronic fatigue syndrome of childhood and in juvenile idiopathic arthritis. Psychological Medicine, 2003, 33, 2, 289-297.
High rates of psychopathology and of personality problems have been reported in children and adolescents with CFS. It is not clear whether this is consequent on the experience of chronic physical ill health. We compare psychiatric adjustment in children with CFS and in children suffering from another chronic physical disorder (juvenile idiopathic arthritis or JIA).
Our sample consisted of 28 children with CFS (Oxford and CDC criteria '94) and 30 with JIA attending tertiary paediatric centres (age range, 11 to 18 years, mean 15, duration CFS = 2.9 years and JIA 9.8 years). In order to assess psychiatric status and functioning, we used the K-SADS psychiatric interviews, CGAS and Harter Self-Esteem Questionnaire with child subjects; behavioural questionnaires (CBCL) and child personality assessment interviews (PAS) with parent informants.
Psychiatric disorders in the year prior to interview had been present significantly more often in the CFS group (72% v. 34% in JIA) and were more impairing to them (CGAS scores of 45 v. 77). Most common diagnoses in both groups were depressive and anxiety disorders. Personality problems were also significantly more frequent in CFS subjects (48% disorder and 26% difficulty v. 11% and 11% in JIA). There were few differences between the two groups in self-esteem. There were no significant differences in current psychiatric disorders, psychiatric co-morbidity (previous week), social problems, delinquent behaviour, and social performance at school. In terms of personality, CFS patients were much more sensitive, anxious, dependent, and vulnerable. Few had pre-morbid emotional and behavioural problems (only a fifth of subjects).
Psychopathology and personality problems are common in children and adolescents with severe forms of CFS ...
[Ed. note: There is no information on the type of symptoms reported by the subjects, or their severity. There is no information e.g. from parents, as to why the children might have been more sensitive and had periods of psychiatric disorder following the onset of their illness.]
Smith, MS., Martin-Herz, SP., Womack, WM and Marsigan, JL. Comparative study of anxiety, depression, somatization, functional disability, and illness attribution in adolescents with chronic fatigue or migraine. Pediatrics, 2003, 111, 4, E376-E381.
Taillefer, SS., Kirmayer, LJ., Robbins, JM and Lasry, JC. Correlates of illness worry in chronic fatigue syndrome. Journal of Psychosomatic Research, 2003, 54, 4, 331-337.
Anxiety about illness leading to restriction of activity and physical deconditioning has been hypothesized to contribute to the chronicity of fatigue. Pathological symptom attributions, personality traits, and depression have all been hypothesized to contribute to illness worry.
We compared 45 people with CFS (CDC criteria '88) and 40 multiple sclerosis (MS) outpatients using a battery of psychometric instruments comprising the 12-item Illness Worry scale, the Symptom Interpretation Questionnaire (SIQ), the NEO Five-Factor Inventory (NEO-FFI), and a modified version of the SCL-90R Depression scale.
There was no difference between the two diagnostic groups on neuroticism, depressive symptoms, or the three scales of the SIQ. On the illness worry index, the CFS group had significantly higher scores than the MS group. This difference was due to items tapping vulnerability to illness and the perception that others are not taking their illness seriously. Somatic attributional style, neuroticism, depressive symptoms, and age were all significant predictors of illness worry in both CFS and MS patients.
Somatic attributions, neuroticism, and depression all contribute to illness worry in chronic illness. However, these factors do not account for the higher levels of illness worry in CFS as opposed to MS, which may be due to other specific cognitive and social interactional processes.
Jason, LA., Helgerson, J., Torres-Harding, SR., Carrico, AW and Taylor RR. Variability in diagnostic criteria for chronic fatigue syndrome may result in substantial differences in patterns of symptoms and disability. Evaluation and the Health Professions, 2003, 26, 1, 3-22.
CFS is an illness that involves severe, prolonged exhaustion as well as neurologic, immunologic, and endocrine system pathology. Because the pathogenesis of CFS has yet to be determined, case definitions have relied on clinical observation in classifying signs and symptoms for diagnosis. The current investigation examined differences between CFS as defined by Fukuda et al and a set of criteria that has been stipulated for myalgic encephalomyelitis (ME)*. Dependent measures included psychiatric comorbidity, symptom frequency, symptom severity, and functional impairment. Those meeting the ME (n=17) and Fukuda et al. (1994) criteria (n=18) were compared with a group having chronic fatigue due to psychiatric reasons (n=33).
Significant differences occurred primarily with neurologic, neuro-psychiatric, fatigue/weakness, and rheumatological symptoms. Neuropsychological symptoms more commonly reported in the ME group included sensitivity to lights, inability to concentrate, difficulty retaining information, slow to process visual or auditory information, feeling weak or dizzy after standing and dizziness when moving the head. The ME group was more impaired in terms of symptom frequency but there were no differences between the ME and CFS groups in terms of disability (MOS) and psychiatric impairment. There was less post-exertional malaise in both the CFS and CFS-psychiatric groups.
These findings suggest that it might be inappropriate to synthesize results from studies of this illness that use different definitions to select study populations.
[Ed. note: ME was diagnosed if there was a presence of post-exertional malaise, plus memory and concentration problems, and fluctuation of symptoms. The London criteria for ME are more specific and focus on fatigability after minimal exertion plus a delay in the recovery of muscle power after exertion ends, as well as evidence of CNS involvement (not just in terms of cognitive impairment) plus fluctuation in the severity of symptoms. It is therefore possible that the actual differences between ME and CFS patients are even more pronounced.]
Skapinakis, P., Lewis, G and Mavreas, V. Unexplained fatigue syndromes in a multinational primary care sample: specificity of definition and prevalence and distinctiveness from depression and generalized anxiety. American Journal of Psychiatry, 2003, 160, 4, 785-787.
The authors investigated whether "narrow" definitions of unexplained fatigue syndromes that require additional minor somatic symptoms are more strongly associated with psychiatric morbidity than wider ones. This was a secondary analysis of the World Health Organization Collaborative Project on Psychological Problems in General Health Care. A total of 5,438 primary care patients from 14 countries were assessed with the Composite International Diagnostic Interview.
The prevalence of fatigue syndromes fell from 7.99 to 1.69 as somatic criteria* were added. Patients with depression or anxiety were more likely to report unexplained fatigue, but this association was stronger for definitions of unexplained fatigue with more somatic criteria.
"Definitions of unexplained fatigue syndromes that require more somatic criteria selected more patients with psychiatric disorders in this culturally diverse sample."
[Ed. note: The somatic symptoms in this instance were headache, pain, unrefreshed sleep plus impaired concentration and memory. There is no indication whether other listed symptoms of CFS e.g. sore throats, were assessed. There is no data about the severity of illness and its correlation with psychiatric morbidity. The criteria for fatigue may have included people who were tired all the time 'in the past month'. Substantial fatigue was assessed but not defined. It is not clear how researchers classified patients with neurological symptoms typical of ME. There is no information as to when the psychiatric disorders began relative to CFS or whether symptoms such as fatigue and impaired concentration were removed when diagnosing disorders like depression (cf. confounding). In short, the CFS here is not identical to CFS as currently defined. 80% may have comorbid anxiety and depression but whether this is also relevant to strictly defined CFS is unclear. Given the use of broad criteria, it is difficult to follow claims relating to the alleged problems of 'narrow definitions'.]
Lerner, AM., Beqaj, SH., Deeter, RG., Dworkin, HJ., Zervos, M., Chang, CH., Fitzgerald, JT., Goldstein, J and O'Neill, W. A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs Today (Barc), 2002, 38, 8, 549-561.
This study was designed to determine safety and efficacy of a 6-month trial of valacyclovir in single-virus Epstein-Barr virus (EBV) persistent infection.
The authors concluded that the 16 CFS patients (included in both phases of this study) with EBV-persistent infection (EBV single-virus subset) were improved after 6 months of continuous pharmacokinetic dosing with valacyclovir. Nine CFS patients with EBV/human CMV co-infection did not benefit from 6 months of similar treatment. Valacyclovir is not an effective anti-human CMV anti-viral drug. Unimproved CFS patients with co-infections EBV and human CMV may require combined treatment with valacyclovir and another drug more active against human cytomegalovirus.
Cleare, AJ. The neuroendocrinology of chronic fatigue syndrome. Endocrine Reviews, 2003, 24, 2, 236-252.
Review focusing on the HPA axis; although the quality of many studies is poor, the overall balance of evidence points to reduced cortisol output in at least some patients, with some evidence that this is linked to symptom production or persistence. There is evidence for heightened negative feedback and glucocorticoid receptor function and for impaired ACTH and cortisol responses to a variety of challenges. However, there is no evidence for a specific or uniform dysfunction of the HPA axis.
Given the many factors that may impinge on the HPA axis in CFS, such as inactivity, sleep disturbance, psychiatric comorbidity, medication, and ongoing stress, it seems likely that HPA axis disturbance is heterogeneous and of multifactorial etiology in CFS.
Studies assessing GH, dehydroepiandrostenedione and its sulfate, melatonin, leptin, and neuroendocrine-monoamine interactions are also reviewed. There is some evidence from these studies to suggest alterations of dehydroepiandrostenedione sulfate function and abnormal serotonin function in CFS, but whether these changes are of functional importance remains unclear. To obtain a clearer assessment of the etiological and pathophysiological relevance of endocrine changes in CFS, it is suggested that more prospective cohort studies be undertaken in groups at high risk for CFS, that patients with CFS are followed up into recovery, and that multidimensional assessments are undertaken to unravel the influence of the various confounding factors on the observed endocrine changes in CFS.
Amel Kashipaz, MR., Swinden, D., Todd, I and Powell, R. Normal production of inflammatory cytokines in chronic fatigue and fibromyalgia syndromes determined by intracellular cytokine staining in short-term cultured blood mononuclear cells. Clinical and Experimental Immunology, 2003, 132, 2, 360-365.
It has been proposed that cytokines play a role in the pathogenesis of CFS and fibromyalgia syndrome (FMS). However, different studies have reported conflicting results using enzyme-linked immunosorbent assay or polymerase chain reaction to detect cytokines in these conditions.
In the present study, for the first time, the production of inflammatory [interleukin (IL)-1á, IL-6, and TNF-á] and anti-inflammatory (IL-10) cytokines by CD14+ and CD14- PBMC from CFS and FMS patients and sex- and age-matched normal subjects was investigated at the level of individual cells using the technique of intracellular cytokine staining and flow cytometry. Cultures were carried out in the presence of polymyxin B to inhibit the effect of endotoxins on cytokine production by monocytes. The mean intensity of fluorescence (MIF) and percentage of CD14+ (monocytes) and CD14- (lymphocytes) cytokine-producing mononuclear cells were comparable in patients and controls in either unstimulated or IFN-gamma-stimulated conditions.
Our study indicates that dysregulation of cytokine production by circulating monocytes or non-monocytic cells (lymphocytes) is not a dominant factor in the pathogenesis of CFS/FMS.
Assefi, NP., Coy, TV., Uslan, D., Smith, WR and Buchwald, D. Financial, occupational, and personal consequences of disability in patients with chronic fatigue syndrome and fibromyalgia compared to other fatiguing conditions. Journal of Rheumatology, 2003, 30, 4, 804-808.
Badawy, AAB., Morgan, CJ., Llewelyn MB, et al. The serotonin status of patients with the chronic fatigue syndrome: A preliminary study. Journal of Psychopharmacology, 2002, 16 (3): D4 Suppl.
Eidelman, D. Chronic fatigue syndrome - medical fact or artifact. Medical Hypotheses, 2003, 60, 6, 840-842.
Short paper discussing two impediments to the understanding of CFS. Firstly, "although fatigue is central to CFS, medical scientists appear not to understand what fatigue itself really is, nor what is its purpose or mode of function. A functional definition of fatigue is suggested to help resolve this.
Secondly, physicians and other researchers - psychologists and alternative medicine practitioners - fail to observe an elementary and fundamental procedure of clinical medicine, namely, that of properly examining their patients before making a diagnosis or providing treatment. Recognizing the existence of these impediments is considered a self-evident precondition for further significant progress being made in this field."
Englebienne, P., Verhas, M., Herst, CV and De Meirleir, K. Type I interferons induce proteins susceptible to act as thyroid receptor (TR) corepressors and to signal the TR for destruction by the proteasome: possible etiology for unexplained chronic fatigue. Medical Hypotheses, 2003, 60, 2, 175-180.
In some patients complaining of chronic fatigue such as those suffering from the CFS, no underlying physical cause can be clearly identified and they typically present a normal thyroid function. Several studies indicate a dysregulation in the type I interferons (IFN-alpha/beta) pathway in CFS resulting in a sustained up-regulation of 2('),5(')-oligoadenylate synthetases (2-5OAS).
Likewise, patients treated with IFN-alpha/beta usually complain of severe fatigue as a limiting side effect. Beside the 2-5OAS, IFN-alpha/beta induce also the expression of three closely related proteins of unknown function termed the 2-5OAS-like (2-5OASL) proteins. The amino acid sequences of the 2-5OASL proteins display 96% identity with the partial sequence of the thyroid receptor interacting protein (TRIP) 14, further contain two typical thyroid hormone receptor (TR) coregulator domains and feature two ubiquitin C-terminal domains. From these observations, we raise the hypothesis that the 2-5OASL proteins are TRIPs capable of, respectively, repressing TR transactivation and/or signaling the receptor for destruction by the proteasome. Such molecular mechanisms could explain the development of a clinical hypothyroid state in presence of a normal thyroid function.
Fisher, M., Krilov, LR and Ovadia, M. Chronic fatigue syndrome and eating disorders: concurrence or coincidence? International Journal of Adolescent Medical Health, 2002, 14, 4, 307-316.
This article discusses four patients who were found to have both an eating disorder and the CFS. Two of the patients presented for evaluation of an eating disorder and also had CFS, while two of the patients presented for evaluation of CFS and also had an eating disorder. In all four patients the eating disorder preceded the CFS. We consider the question of whether the occurrence of these two disorders in the same patients is merely a coincidence; whether an eating disorder can act as a precipitant for CFS, perhaps through the exacerbation of an underlying vascular instability; and whether overlapping etiologies may predispose some adolescents to develop both disorders.
Friedberg, F. Does graded activity increase activity? A case study of chronic fatigue syndrome. Journal of Behavior Therapy and Experimental Psychiatry, 2002, 33, 3-4, 203-215.
The reliance on self-report outcome measures in clinical trials of graded activity-oriented CBT in CFS makes it difficult to draw definitive conclusions about actual behavioral change. The participant in this case study was a 52-year-old married male with CFS (CDC criteria '94) who was working full-time. Outcome measures included a step counter to objectively measure physical activity as well as a daily diary measure of exercise activity and in vivo ratings of perceived energy, fatigue, and affect. The following psychometric instruments were also used: the CFS Symptom Inventory, the SF-36, the Beck Depression Inventory, and the Beck Anxiety Inventory. The 26-session graded activity intervention involved gradual increases in physical activity.
From baseline to treatment termination, the patient's self-reported increase in walk time from 0 to 155 min a week contrasted with a surprising 10.6% decrease in mean weekly step counts. The final follow-up assessment revealed a "much improved" global rating, substantial increases in patient-recorded walk time and weight lifting intensity, yet a relatively modest increment in weekly step counts. It appeared that improvement was associated with mood-enhancing, stress-reducing activities that were substituted for stress-exacerbating activities.
[Ed. note: This patient had a fear of relapsing, which was well-founded as at a certain stage, he reached a plateau. He may have reduced overtime and paced activities better. It is therefore of use to differentiate high and low functioning patients.
The paper also includes previously unpublished information about the trial by Prins et al. 2001. According to Bleijenberg (pers. comm., the patients treated with CBT\GET showed no change in actigraph-measured activity from pre-treatment baseline to treatment termination and follow-up assessments. This again shows the discrepancy between self-reports of improvement and objective measures of activity.]
Ghosh, AK and Ghosh, K. The head-up tilt test for diagnosing chronic fatigue syndrome. Quarterly Journal of Medicine, 2003, 96, 379-380. (Letter)
Hyams, KC. The investigation of chronic fatigue syndrome: a case-study of the limitations of inductive inferences and non-falsifiable hypotheses in medical research. Medical Hypotheses, 2003, 60, 5, 760-766.
Jason, L.A., Taylor, R.R., Kennedy, C.L., Jordan, K.M., Song, S., Johnson, D., & Torres-Harding, S. Chronic fatigue syndrome: Symptom subtypes in a community based sample. Women & Health, 2003, 37, 1-13.
Most studies of CFS have been based on patients recruited from primary or tertiary care settings. Patients from such settings might not be typical of patients in the general population. The present investigation involved examining individuals with CFS from a community-based study.
A random sample of 18,675 respondents in Chicago were first interviewed by telephone. A group of individuals with chronic fatigue accompanied by at least four Fukuda et al. (1994) symptoms associa-ted with CFS were given medical and psychiatric examinations. From this sample, a physician review group diagnosed individuals with CFS. Those diagnosed with CFS were subclassified based on frequency of symptoms.
Important differences emerged on measures of socio-demographics and disability. For instance, those with low frequency of symptoms (up to 13 from a list of 66) were younger and more likely to be working full-time than those with a high frequency of symptoms. Conversely, the high frequency group were more likely to have children, had more problems with physical functioning, and reported more perceived stress. The groups did not differ with respect to psychiatric disorders.
Logan, AC., Venket, Rao A and Irani, D. Chronic fatigue syndrome: lactic acid bacteria may be of therapeutic value. Medical Hypotheses, 2003, 60, 6, 915-923.
Recent research shows that patients with CFS have marked alterations in microbial flora, including lowered levels of bifido-bacteria and small intestinal bacterial overgrowth (SIBO). Research also indicates that CFS patients are under increased oxidative stress, have a type 2 helper cell dominated cytokine profile, frequently report allergies, have altered essential fatty acid (EFA) status and may have malabsorption of certain micro-nutrients.
Lactic acid bacteria (LAB) have the potential to influence the immune system in CFS patients by supporting T helper cell 1 driven cellular immunity and may decrease allergies. In addition LAB are strong antioxidants, may improve EFA status, can enhance absorption of micronutrients by protecting the intestinal epithelial barrier, and have been used to treat SIBO. It is our contention that LAB may have a therapeutic role in the treatment of CFS.
McCrone, P., Darbishire, L., Ridsdale, L and Seed, P. The economic cost of chronic fatigue and chronic fatigue syndrome in UK primary care. Psychological Medicine, 2003, 33, 2, 253-261.
Patients presenting to general practitioners with unexplained chronic fatigue were recruited to the study. Service use over a 3 month period was measured and lost employment recorded. These data were used to estimate economic costs. Patients with CFS were compared to patients with only chronic fatigue using a multiple regression model with sample differences controlled.
The mean total cost of services and lost employment across the sample was £1906 for the 3-month period with formal services accounting for 9.3% of this figure. Service use was higher for patients with CFS compared to those with chronic fatigue alone. Total 3-month costs were on average higher for CFS (£3515 v. £1176) but when sample differences were taken account of the mean difference was reduced to £1406 (p=0.086). Over 90% of the cost was accounted for by care provided by friends and family members and by lost employment. Patients with dependants had significantly higher costs than those with none and costs were also significantly higher for greater levels of functional impairment.
"Chronic fatigue imposes substantial economic costs on society, mainly in the form of informal care and lost employment. Treatments need to be developed which recognize these impacts."
McCue, P., Scholey, AB and Wesnes, KA. Cognitive deficits in chronic fatigue syndrome: Effects related to symptom severity but not to depressive symptomatology. Journal of Psychopharmacology, 2002, 16, 3, D2 Suppl.
McCue, P., Scholey, AB and Wesnes, KA. Cognitive impairment in chronic fatigue syndrome in relation to cognitive factors derived from the CDR assessment system. Journal of Psychopharmacology, 2002, 16 (3): D3 Suppl.
Naschitz, JE., Rosner, I., Rozenbaum, M., Naschitz, S., Musafia-Priselac, R., Shaviv, N., Fields, M., Isseroff, H., Zuckerman, E., Yeshurun, D and Sabo, E. The head-up tilt test with haemodynamic instability score in diagnosing chronic fatigue syndrome. Quarterly Journal of Medicine, 2003, 96, 2, 133-142.
Nijs, J., Vaes, P., McGregor, N., Van Hoof, E and De Meirleir, K. Psychometric properties of the Dutch chronic fatigue syndrome-activities and participation questionnaire (CFS-APQ). Physical Therapy, 2003, 83, 5, 444-454.
Page, LA and Wessely, S. Medically unexplained symptoms: exacerbating factors in the doctor-patient encounter. Journal of the Royal Society of Medicine, 2003, 96, 223-227.
[Ed. note: Article insinuating that patients with medically unexplained symptoms, including CFS, are largely ill or disabled because of prejudiced ideas, faulty beliefs and stupidity, and that doctors collude with them. This article ignores a lot of information which undermines their argument, and may thus be seen as misleading.]
Pinching, AJ. AIDS and CFS/ME: a tale of two syndromes. Clinical Medicine, 2003, 3, 1, 78-82.
Both HIV/AIDS and CFS/ME presented major challenges for medicine, science and society. This article explores what could have impeded investigation of - and specifically pharmaceutical engagement with - CFS/ME, in contrast to the impressive achievements seen in HIV/AIDS... Nothing of real substance is identified that would justify the lack of investment and interest in solutions for patients with CFS/ME.
Sabin, TD. An approach to chronic fatigue syndrome in adults. The Neurologist, 2003, 9, 28-34.
Short account which portrays CFS in terms of neurasthenia. The author advocates that postviral fatigue be retained as a "separate category". He notes the alcohol intolerance associated with the latter.
Stewart, CC., Cookfair, DL., Hovey, KM., Wende, KE., Bell, DS and Warner, CL. Predictive immunophenotypes: Disease-related profile in chronic fatigue syndrome. Cytometry Part B: (Clinical Cytometry), 2003, 53B, 1, 26-33.
This study compared 90 people with CFS (CDC criteria '88 and '94) with 50 healthy controls, from two different areas of Upstate New York. One group was from a metropolitan area with no known cluster of cases; the other from a small town with a cluster. Aside from collecting immune phenotype data (NK cells, cytotoxic T-cell markers), measures included the Sickness Impact Profile (SIP).
There were differences between the patients from both areas and controls from the metropolitan area. However, the controls from the town with clusters showed many of cytotoxic T-cell phenotypes documented in the cases. Only the number of CD56+CD3-CD8+ cells (a NK cell subset) was different from the controls (p=.022). Higher SIP scores were associated with reduced levels of NK cells.
NK cell function may play an important role in preventing the develpment of CFS in individuals from an area with clusters. Differences in controls from cluster and noncluster areas may explain some of the inconsistencies in findings from other studies.
Swinkels, DW., Aalbers, N., Elving, LD., Bleijenberg, G., Swanink, CM and van der Meer, JW. Primary haemochromatosis: a missed cause of chronic fatigue syndrome? Netherlands Journal of Medicine, 2002, 60, 11, 429-433.
In a group of 88 CFS patients we could exclude primary haemochomatosis (PH) in all but two of them (prevalence 2.3%; 95% confidence interval 0-5.5%). In our population of CFS patients PH is not more common than in a control population of northern European descent (prevalence 0.25-0.50%).
Szyndler, JE., Towns, S., Hoffman, RC and Bennett, DL. Clinical assessment, management and outcomes of a group of adolescents presenting with complex medico-psychosocial conditions. Annals of Academic Medicine, Singapore, 2003, 32, 1, 51-57.
Tarello, W. Immunological anomalies and thrombocytopenia in 117 dogs and cats diagnosed with chronic fatigue syndrome (CFS). Acta Vet Hung, 2003, 51, 1, 61-72.
Abnormalities documented in cats and dogs with 'CFS'
Van Duyse, A., Mariman, A., Poppe, C., Michielsen, W and Rubens, R. Chronic fatigue in the psychiatric practice. Acta Neuropsychiatrica, 2002, 14, 3, 127-133.
[Ed.note: This account is biased towards psychiatric variables.]
Vernon, SD., Unger, ER., Dimulescu, IM., Rajeevan, M and Reeves, WC. Utility of the blood for gene expression profiling and biomarker discovery in chronic fatigue syndrome. Disease Markers, 2002, 18, 4, 193-199.
The objective of this study was to determine if gene expression profiles of PMBCs could distinguish between subjects with CFS and healthy controls. Total RNA from PBMCs of five CFS cases and 17 controls was labeled and hybridized to 1764 genes on filter arrays. Gene intensity values were analyzed by various classification algorithms and nonparametric statistical methods. The classification algorithms grouped the majority of the CFS cases together, and distinguished them from the healthy controls. Eight genes were differentially expressed in both an age-matched case-control analysis and when comparing all CFS cases to all controls. Several of the differentially expressed genes are associated with immunologic functions (e.g., CMRF35 antigen, IL-8, HD protein) and implicate immune dysfunction in the pathophysiology of CFS. These results successfully demonstrate the utility of the blood for gene expression profiling to distinguish subjects with CFS from healthy controls and for identifying genes that could serve as CFS biomarkers.
Skapinakis, P., Lewis, G and Mavreas, V. Cross-cultural differences in the epidemiology of unexplained fatigue syndromes in primary care. British Journal of Psychiatry, 2003, 182, 3, 205-209.
Study focusing on fatigue of 1 month duration in different countries.
The prevalence ranged from 2.26% (Ibadan) to 15.05% (Manchester). Fatigue as presenting complaint to the GP ranged from 0.19% (Manchester) to 17.02 (Bangalore).
[Ed. note: The authors speculate about fatigue as an indicator of unmet psychiatric needs but not based on information offered by subjects and discussed in the paper.]
Singh, A., Naidu, PS., Gupta, S and Kulkarni, SK. Effect of natural and synthetic antioxidants in a mouse model of chronic fatigue syndrome. Journal of Med Food, 2002, 5, 4, 211-220.
In the present study, a mouse model of CFS was used in which mice were forced to swim for one 6-minute session on each day for 15 days and the immobility period was recorded. There was a significant increase in immobility period in saline-treated mice on successive days. Intraperitoneal treatment with the potent anti-oxidants carvedilol (5 mg/kg) and melatonin (5 mg/kg) produced a significant reduction in immobility period. Similar results were observed with herbal preparations administered orally: Withania somnifera (100 mg/kg), quercetin (50 mg/kg), and St. John's wort (Hypericum perforatum L., 10 mg/kg).
Biochemical analysis revealed that chronic swimming significantly induced lipid peroxidation and decreased glutathione (GSH) levels in the brains of mice. The rats also showed decreased levels of antioxidant defense enzymes, superoxide dismutase (SOD), and catalase. Co-administration of antioxidants carvedilol, melatonin, W. somnifera, quercetin or St. John's wort significantly reduced lipid peroxidation and restored the GSH levels decreased by chronic swimming in mice. Further, the treatment increased levels of SOD in the forebrain and of catalase.
The findings suggest that oxidative stress may play a role in the pathophysiology of CFS and that antioxidants could be useful in the treatment of CFS.
Artsimovich, NG., Galushina, TS., Matvienko, MA., Nastoyaschaya, NN., Fadeeva, TA and Shneidorova, MA. Immunity impairment as a result of neurohormonal disorders. Russian Journal of Immunology, 1999, 4, 4, 343-345.
Non-factual information and repetition of findings in abstracts have been omitted from some abstracts.
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