Number 4 |
1st November 2007 |
VIROLOGY
|
Chia, JKS and Chia, AY. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. Journal of Clinical Pathology, 2007, Online first: 13th September. doi: 10.1136/jcp.2007.
The aetiology for CFS remains elusive although enteroviruses have been implicated as one of the causes by a number of studies. Since most CFS patients have persistent or intermittent gastro-intestinal (GI) symptoms, the presence of viral capsid protein 1 (VP1), enterovirus (EV) RNA and culturable virus in the stomach biopsy specimens of patients with CFS was evaluated.
Sample: 165 consecutive patients with CFS (CDC criteria ‘2003) underwent upper GI endoscopies and antrum biopsies. Immunoperoxidase staining was performed using EV-specific monoclonal antibody (mAb) or a control mAb specific for cytomegalovirus (CMV). RT-PCR ELISA was performed on RNA extracted from paraffin sections or samples preserved in RNA later. Biopsies from normal stomach and other gastric diseases served as controls. 75 samples were cultured for EV.
135/165 (82%) biopsies stained positive for VP1 within parietal cells, whereas 7/34 (20%) of the controls stained positive (p<0.001). CMV mAb failed to stain any of the biopsy specimens. Biopsies taken from six patients at the onset of the CFS/abdominal symptoms and 2–8 years later showed positive staining in the paired specimens. EV RNA was detected in 9/24 (37%) paraffin-embedded biopsy samples; 1/21controls had detectable EV RNA (p<0.01); 1/3 patients had detectable EV RNA from two samples taken 4 years apart; 5 patient samples showed transient growth of non-cytopathic enteroviruses.
Enterovirus VP1, RNA and non-cytopathic viruses were detected in the stomach biopsy specimens of CFS patients with chronic abdominal complaints. A significant subset of CFS patients may have a chronic, disseminated, non-cytolytic form of enteroviral infection, which could be diagnosed by stomach biopsy.
[Note: The full text of this article is currently available for free at:
http://press.psprings.co.uk/jcp/september/cp50054.pdf
See also commentary by JR Kerr. Enterovirus infection of the stomach in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Ibid 14th September.
Niblett, SH., King, KE., Dunstan, RH., Clifton-Bligh, P., Hoskin, LA., Roberts, TK., Fulcher, GR., McGregor, NR., Dunsmore, JC., Butt, HL., Klineberg, I and Rothkirch TB. Hematologic and urinary excretion anomalies in patients with chronic fatigue syndrome. Experimental Biology and Medicine, (Maywood), 2007, 232, 8, 1041-1049.
Patients with CFS have a broad and variable spectrum of signs and symptoms with variable onsets. This report outlines the results of a single-blind, cross-sectional research project that extensively investigated a large cohort of 100 CFS patients (Oxford definition) and 82 non-fatigued control subjects with the aim of performing a case-control evaluation of alterations in standard blood parameters and urinary amino and organic acid excretion profiles.
Blood biochemistry and full blood counts were unremarkable and fell within normal laboratory ranges. However, the case-control comparison of the blood cell data revealed that CFS patients had a significant decrease in red cell distribution width and increases in mean platelet volume, neutrophil counts, and the neutrophil-lymphocyte ratio. Evaluation of the urine excretion parameters also revealed a number of anomalies. The overnight urine output and rate of amino acid excretion were both reduced in the CFS group (p<0.01). Significant decreases in the urinary excretion of asparagine (p<0.0001), phenylalanine (p<0.003), the branch chain amino acids (p<0.005), and succinic acid (p<0.0001), as well as increases in 3-methylhistidine (p<0.05) and tyrosine (p<0.05) were observed. It was concluded that the urinary excretion and blood parameters data supported the hypothesis that alterations in physiologic homeostasis exist in CFS patients.
“The major blood cell parameter that differentiated CFS patients from the control group was an increase in the neutrophil count (p<0.05). Increases in circulating neutrophils have been commonly observed in inflammation and in localized or generalized bacterial infections, especially with pyogenic bacteria, and are sometimes accompanied by fever due to release of leucocyte pyrogens. The augmented neutrophil count lead to an increased neutrophil-lymphocyte ratio, suggestive of a nonviral pathogen-like stimulus. In addition, the mean RDW [red cell distribution width] “was decreased in CFS patients compared with healthy individuals (p<0.05). RDW represents a sensitive measure of variation in red cell shape or anisocytosis. These changes may reflect alterations in red cell morphology, possibly as a result of oxidative damage as proposed by Richards et al. and are consistent with previous reports of altered erythrocyte morphology and rheology in patients with CFS.” [References removed, Ed].
Bogaerts, K., Hubin, M., Van Dies, I., De Peuter, S., Van Houdenhove, B., Van Wambeke, P., Crombez, G and Van den Bergh, O. Hyperventilation in patients with chronic fatigue syndrome: The role of coping strategies. Behaviour Research and Therapy, 2007, 45, 11, 2679-2690.
Hyperventilation has been suggested as a concomitant and possible maintaining factor that may contribute to the symptom pattern of CFS. Because patients accepting the illness and trying to live with it seem to have a better prognosis than patients chronically fighting it, we investigated breathing behavior during different coping response sets towards the illness in treatment-seeking, female patients with CFS (N=30, CDC ’94 criteria).
Patients imagined a relaxation script (baseline), a script describing a coping response of hostile resistance, and a script depicting acceptance of the illness and its (future) consequences. During each imagery trial, end-tidal PCO2 (Handheld Capnograph, Oridion) was measured. After each trial, patients filled out a symptom checklist. Results showed low resting values of partial pressure of CO2 (PetCO2) overall, while only imagery of hostile resistance triggered a decrease and deficient recovery of PetCO2. Also, more hyperventilation complaints and complaints of other origin were reported during hostile resistance imagery compared with acceptance and relaxation. “Our results suggest that occasional hyperventilation may occur in CFS patients, especially in conditions of hostile resistance.”
In conclusion, hostile resistance seems to trigger both physiological and symptom perception processes contributing to the clinical picture of CFS. “Our results suggest that the promotion of acceptance as a coping strategy may have good additive value to the existing revalidation program, which currently consists of traditional cognitive behavioral therapy and graded exercises.”
[Ed. Note: The lack of control group makes it difficult to link the findings to the illness CFS, as opposed to feeling unwell. Studies in the laboratory may not reflect experiences in real life. Results may also vary with experience; information and advice may positively affect appraisal and coping.]
Boneva, RS., Decker, MJ., Maloney, EM., Lin, JM., Jones, JF., Helgason, HG., Heim, CM., Rye, DB and Reeves, WC. Higher heart rate and reduced heart rate variability persist during sleep in chronic fatigue syndrome: A population-based study. Autonomic Neuroscience: Basic and Clinical, 2007 Sep 10; [Epub ahead of print]. doi:10.1016/j.autneu.2007.08.002.
Autonomic nervous system (ANS) dysfunction has been suggested in patients with CFS. In this study, we sought to determine whether increased heart rate (HR) and reduced heart rate variability (HRV) parameters observed in CFS patients during wakefulness persist during sleep. To this end, we compared heart rate (HR) and HRV as indicators of ANS function in CFS subjects (CDC criteria ’94) and non-fatigued (NF) controls in a population-based, case-control study. Thirty subjects with CFS and 38 NF controls, matched for age-, sex- and body mass index, were eligible for analysis. Main outcome measures included mean RR interval (RRI), HR, and HRV parameters derived from overnight ECG. Plasma aldosterone and norepinephrine levels, medicines with cardiovascular effect, and reported physical activity were examined as covariates. General Linear Models were used to assess significance of associations and adjust for potential confounders.
Compared to controls, CFS cases had significantly higher mean HR (71.4 vs 64.8 bpm), with a shorter mean RRI [840.4 (85.3) vs 925.4(97.8) ms] (p<0.0004, each), and reduced low frequency (LF), very low frequency (VLF), and total power (TP) of HRV (p<0.02, all). CFS cases had significantly lower plasma aldosterone (p<0.05), and tended to have higher plasma norepinephrine levels. HR correlated weakly with plasma norepinephrine (r=0.23, p=0.05) and moderately with vitality and fatigue scores (r=-0.49 and 0.46, respectively, p<0.0001). Limitation in moderate physical activity was strongly associated with increased HR and decreased HRV. Nevertheless, among 42 subjects with similar physical activity limitations, CFS cases still had higher HR (71.8 bpm) than respective controls (64.9 bpm), p=0.023, suggesting that reduced physical activity could not fully explain CFS-associated differences in HR and HRV. After adjusting for potential confounders, case-control differences in HR and TP remained significant (p<0.05).
The presence of increased HR and reduced HRV in CFS during sleep coupled with higher norepinephrine levels and lower plasma aldosterone suggest a state of sympathetic ANS predominance and neuroendocrine alterations. Future research on the underlying pathophysiologic mechanisms of the association is needed
Harvey, SB., Wadsworth, M., Wessely, S and Hotopf, M. The relationship between prior psychiatric disorder and chronic fatigue: evidence from a national birth cohort study. Psychological Medicine, 2007, Nov 2;1-8 [Epub ahead of print].
doi: 10.1017/S0033291707001900.
Increased rates of psychiatric disorder have previously been reported in those diagnosed with CFS or myalgic encephalomyelitis (ME), although the direction of causation in this relationship has not been established. We aimed to test the hypothesis that individuals with self-reported CFS/ME have increased levels of psychiatric disorder prior to the onset of their symptoms.
A total of 5362 participants were prospectively followed with various measures of personality (including neuroticism), psychiatric disorder and fatigue levels collected over the first 43 years of their life. CFS/ME was identified through self-report during a semi-structured interview at age 53 years.
Thirty-four (1.1%) of the 3035 subjects assessed at age 53 years reported a diagnosis of CFS/ME. CFS/ME was more common among females, but there was no association between CFS/ME and either social class, social mobility or educational level. Those with psychiatric illness between the ages of 15 and 36 years were more likely to report CFS/ME later in life with an odds ratio (OR, adjusted for sex) of 2.65 [95% confidence interval (CI) 1.26-5.57,
p=0.01]. Increased levels of psychiatric illness, in particular depression and anxiety, were present prior to the occurrence of fatigue symptoms. There was a dose-response relationship between the severity of psychiatric symptoms and the likelihood of later CFS/ME. Personality factors such as neuroticism were not associated with a self-reported diagnosis of CFS/ME.
This temporal, dose-response relationship suggests that psychiatric disorders, or shared risk factors for psychiatric disorders, are likely to have an aetiological role in some cases of CFS/ME.
[Ed. Note: The self-diagnosis of CFS has been criticised by two of the authors in previous publications. The reliability is unclear, and this is the first paper from these authors which suggests self-diagnosis may be valid. It should be noted that the symptoms of CFS as described in the lay press are also common to several psychiatric disorders, as well as immune related disorders e.g. allergic reactions to food. Given that the CFS population is heterogeneous, it is likely to include a significant number who currently suffer from, are vulnerable to, and experience relapses of various psychiatric disorders. One can only assess the predictive value of variables included in a model and this study appears not to have included a history of allergic sensitivity and infection. Moreover, there is no data on onset (e.g. gradual/post-viral) to clarify the nature of the fatigue syndrome. The onset of CFS (between 41-43) appears to be somewhat later than documented elsewhere. The results might have been more reliable had the researchers also looked at the history of patients with another neurological disorder e.g. MS. If the association between psychiatric history and illness was present in CFS but not in MS, the findings of this study would be more persuasive. Given the limitations of the design, it is possible that the incidence of psychiatric disorders in the CFS population may have been inflated. This study was supported by the MRC.]
Van de Putte, EM., Engelbert, RHH., Kuis, W., Kimpen, JL and Uiterwaal, CSPM. Alexithymia in adolescents with chronic fatigue syndrome. Journal of Psychosomatic Research, 2007, 63, 4, 377-380.
Alexithymia is postulated as an important factor in the development of medically unexplained physical symptoms. It refers to a deficit in cognitive processing and regulation of emotions, characterized by difficulties in describing and differentiating emotions and a cognitive style focused on external events instead of inner experience. CFS is presently medically unexplained. The aim of this study was to investigate whether the prevalence of alexithymia was higher in adolescents with CFS compared to healthy adolescents. Co-morbidity such as anxiety and depression were analyzed as possible confounding factors. Secondly, alexithymia was investigated as a prognostic factor for the recovery of CFS.
A cross-sectional study was performed among 40 adolescent outpatients diagnosed with CFS (CDC criteria ’94) and 36 healthy controls. The 20-item Toronto Alexithymia Scale (TAS) was used to assess all participants for alexithymia. Additionally, all participants completed a number of questionnaires regarding fatigue (Checklist Individual Strength), somatic complaints (Checklist Somatization Inventory), depression (Children's Depression Inventory), and trait anxiety (Spielberger State Trait Anxiety Questionnaire). A follow-up study was performed among the CFS adolescents 1 1/2 years after the initial assessment.
CFS adolescents scored higher only on the TAS subscale identifying feelings [mean difference after adjustment for depression and anxiety 2.8 (95% CI: 0.6; 4.9]. Twelve CFS adolescents (30%) fulfilled criteria for alexithymia. This subgroup was characterized by higher scores for depression and anxiety but equal scores for fatigue and somatic complaints compared to those without alexithymia. At follow-up, 47% had recovered and there were no differences in recovery between the alexithymic and nonalexithymic CFS adolescents.
Alexithymia neither appears to be a unique correlate of CFS nor to be a prognostic factor for recovery of the CFS illness.
Vollmer-Conna, U., Cameron, B., Hadzi-Pavlovic, D., Singletary, K., Davenport, T., Vernon, S., Reeves, WC., Hickie, I., Wakefield, D and Lloyd, AR for the Dubbo Infective Outcomes Study Group. Postinfective fatigue syndrome is not associated with altered cytokine production. Clini-cal Infectious Diseases, 2007, 45, 732-735.
Peripheral blood specimens and clinical data were obtained over a 12-month period from subjects in the Dubbo Infection Outcomes Study to examine cytokine production in post-infective fatigue syndrome. Ex vivo production of 8 cytokines was examined in 22 case patients (PIFS, mean duration of illness = 40 weeks) and in 42 control subjects who recovered promptly. No significant differences were found. Ongoing production of the cytokines examined does not play a role in post-infective fatigue syndrome.
Kogelnik, AM., Loomis, K., Hoegh-Petersen, M., Rosso, F., Hischier, C and Montoya, JG. Use of valganciclovir in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. Journal of Clinical Virology, 2006, 37, Suppl.1, S33-S38.
Twelve patients with long-standing symptoms of central nervous system (CNS) dysfunction and who met the CDC ’94 criteria for CFS were found to have elevated antibody titres to human herpesvirus-6 (HHV-6) and Epstein–Barr virus (EBV). We sought to determine whether elevated antibodies to EBV and HHV-6 indicated chronic viral activation in patients with CNS dysfunction and if their symptoms could be improved by suppressing viral activity with oral valganciclovir.
Patients with high IgG antibody titers against HHV-6 and EBV who were suffering from central nervous system dysfunction and debilitating fatigue for more than one year (median 3 years, range 1-8 years) were treated with 6 months of valganciclovir in an open label study.
Nine out of 12 (75%) patients experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activities. In the nine patients with a symptomatic response to treatment, EBV VCA IgG titers dropped from 1:2560 to 1:640 (p=0.008) and HHV-6 IgG titers dropped from a median value of 1:1280 to 1:320 (p=0.271). Clinically significant hematological toxicity or serious adverse events were not observed among the 12 patients.
These preliminary clinical and laboratory observations merit additional studies to establish whether this clinical response is mediated by an antiviral effect of the drug, indirectly via immunomodulation or by placebo effect.
Sanders, P and Korf, J. Neuroaetiology of chronic fatigue syndrome: An overview. World Journal of Biological Psychiatry, 2007 May 8,1-7 [Epub ahead of print.]
doi: 10.1080/15622970701310971.
CFS is now recognized as a medical disorder. In contrast to recent related reports, the present review focuses primarily on aetiological aspects of CFS. Four major hypotheses are reviewed. (1) Although CFS is often associated with viral infection, the presence of viruses has as yet not consistently been detected. (2) It is not clear whether anomalies of the HPA axis often observed in CFS, are cause or the consequences of the disorder. (3) Immune dysfunction as the cause of CFS is thus far the weakest hypothesis. (4) The psychiatric and psychosocial hypothesis denies the existence of CFS as a disease entity. Accordingly, the fatigue symptoms are assumed to be the consequence of other (somatic) diseases. Other possible causes of CFS are oxidative stress and genetic predisposition. In CFS, CBT is most commonly used. This therapy, however, appears to be ineffective in many patients. The suggested causes of CFS and the divergent reactions to therapy may be explained by the lack of recognition of subgroups. Identification of subtypes may lead to more effective therapeutic interventions.
Amsterdam, JD., Shults, J and Rutherford, N. Open-label study of s-citalopram therapy of chronic fatigue syndrome and co-morbid major depressive disorder. Progress in Neuropsychopharmacology & Biological Psychiatry, 2007 Aug 3; [Epub ahead of print].
doi:10.1016/j.pnpbp.2007.07.019.
CFS is a debilitating disorder with prominent symptoms of malaise, fatigue, myalgia, arthralgia, and impaired concentration. The symptoms of CFS may often overlap those of Major Depressive Disorder (MDD). Treatment of CFS has generally been disappointing. We hypothesized that s-citalopram therapy may improve the symptoms of both disorders in CFS patients with co-morbid depression.
16 patients with CFS (CDC criteria ’94) as well as significant depression (MDD) received s-citalopram 10 mg to 20 mg daily for up to 12 weeks. Outcome measures of CFS included the Chalder Fatigue Questionnaire (CFQ), the multi-dimensional Fatigue Impact Scale (FIS), the CFS symptom rating (CFS-SR) 100 mm visual analogue scale, and the clinical global impressions severity (CGI/S) and change (CGI/C) ratings. Secondary outcomes of MDD included the Hamilton Depression Rating (HAM-D), Beck Depression Inventory (BDI), and the CGI/S and CGI/C ratings of MDD.
We observed reductions in the mean CFQ score (p<0.0005), FIS score (p<0.0005), and CGI/S (p<0.0005) and CGI/C (p<0.0005) ratings over time. There was a significant improvement in 5 of the 8 CFS-SR symptoms: post-exertion malaise (p=0.001), headaches (p<0.0005), unrefreshing sleep (p<0.0005), and impaired memory and concentration (p<0.0005). There was also a reduction in mean HAM-D (p<0.0005), BDI (p<0.0005), CGI/S (p=0.001) and CGI/C (p<0.0005) ratings of MDD. There was less improvement in infection-related symptoms such as tender lymph nodes.
Limitations: The sample size was limited and the study design was not double-blind or placebo controlled.
We observed a significant reduction in both CFS and co-morbid MDD symptom severity ratings, and improvement in 5 of 8 core somatic symptoms of CFS during s-citalopram therapy.
[Ed. note: 14 of the participants were also on other treatments e.g. for diabetes. All the symptoms which responded to treatment are common in depression and there is therefore little evidence that the drug is of value in managing CFS without co-morbid MDD.]
Crawley, EM and Davey Smith, G. Is chronic fatigue syndrome (CFS/ME) heritable in children, and if so why does it matter? Archives of Disease in Childhood, 2007 Sep 5; [Epub ahead of print]. doi:10.1136/adc.2006.110502.
This article looks at the evidence for the heritability of CFS or ME (CFS/ME). The role of genes and the environment and their potential interaction is discussed and the problems with studies in this area are explored. One of the main difficulties with studying CFS/ME is the fact that it is likely to be a heterogeneous condition. We need a clear definition of CFS/ME in children and sample sizes for genetic studies need to be much larger if we are to make an impact in this important area. In the meantime however, paediatricians shouldn't be surprised when they see a family where CFS/ME occurs in more than one person.
Emmert-Streib, F. The chronic fatigue syndrome: a comparative pathway analysis. Journal of Computational Biology, 2007, 14, 7, 961-972.
Review of technique to study biological processes using the gene ontology database.
Evengard, B., Grans, H., Wahlund, E and Nord, CE. Increased number of Candida albicans in the faecal microflora of chronic fatigue syndrome patients during the acute phase of illness. Scandinavian Journal of Gastroenterology, 2007, Sep 18;1-2. In press.
Guo J. Chronic fatigue syndrome treated by acupuncture and moxibustion in combination with psychological approaches in 310 cases. Journal of Traditional Chinese Medicine, 2007, 27, 2, 92-95.
The objective was to observe clinical therapeutic effect of acupuncture and moxibustion combined with a psychological approach on CFS. The treatment was given by acupuncture plus moxibustion combined with a psychological approach based on differentiation of symptoms and signs in 310 cases.
Of 310 cases observed, 275 cases (88.7%) were clinically cured, 28 cases (9%) improved, and 7 cases (2.3%) failed.
Acupuncture plus moxibustion combined with a psychological approach is an effective therapy for CFS.
[Ed. note: Moxibustion, or Moxa for short, is an ancient form of heat therapy.]
Hempel, S., Chambers, D., Bagnall, AM and Forbes, C. Risk factors for chronic fatigue syndrome/myalgic encephalomyelitis: a systematic scoping review of multiple predictor studies. Psychological Medicine, 2007, Sep 25;1-12 [Epub ahead of print].
doi:10.1017/S0033291707001602.
The identification of risk factors for CFS/ME is of great importance to practitioners. A systematic coping review was conducted to locate studies that analysed risk factors for CFS/ME using multiple predictors. We searched for published and unpublished literature in 11 electronic databases, reference lists of retrieved articles and guideline stakeholder submissions in conjunction with the development of a forthcoming national UK guideline. Risk factors and findings were extracted in a concise tabular overview and studies synthesized narratively.
Eleven studies were identified that met inclusion criteria: two case-control studies, four cohort studies, three studies combining a cohort with a case-control study design, one case-control and twin study and one cross-sectional survey. The studies looked at a variety of demographic, medical, psychological, social and environmental factors to predict the development of CFS/ME. The existing body of evidence is characterized by factors that were analysed in several studies but without replication of a significant association in more than two studies, and by studies demonstrating significant associations of specific factors that were not assessed in other studies. None of the identified factors appear suitable for the timely identification of patients at risk of developing CFS/ME within clinical practice.
Various potential risk factors for the development of CFS/ME have been assessed but definitive evidence that appears meaningful for clinicians is lacking.
[Ed. note: the review included studies on patients who did not meet the full criteria for CFS.]
Neu, D., Mairesse, O., Hoffmann, G., Dris, A., Lambrecht, LJ., Linkowski, P., Verbanck, P and Le Bon, O. Sleep quality perception in the chronic fatigue syndrome: correlations with sleep efficiency, affective symptoms and intensity of fatigue. Neuropsychobiology, 2007, 56, 40-46.
One of the core symptoms of the CFS is unrefreshing sleep and a subjective sensation of poor sleep quality. Whether this perception can be expressed, in a standardized questionnaire as the Pittsburgh Sleep Quality Index (PSQI), has to our knowledge never been documented in CFS. Furthermore, correlations of subjective fatigue, PSQI, affective symptoms and objective parameters such as sleep efficiency are poorly described in the literature.
Using a cross-sectional paradigm, we studied subjective measures like PSQI, Fatigue Severity Scale scores and intensity of affective symptoms rated by the Hamilton Depression and Anxiety scales as well as objective sleep quality parameters measured by polysomnography of 28 'pure' (no primary sleep and no psychiatric disorders) CFS patients (CDC criteria ’94, all with unrefreshing sleep) compared to age- and gender-matched healthy controls.
The PSQI showed significantly poorer subjective sleep quality in CFS patients than in healthy controls. In contrast, objective sleep quality parameters, like the Sleep Efficiency Index (SEI) or the amount of slow-wave sleep did not differ significantly. Subjective sleep quality showed a correlation trend with severity of fatigue and was not correlated with the intensity of affective symptoms in CFS. Our findings indicate that a sleep quality misperception exists in CFS or that potential nocturnal neurophysiological disturbances involved in the nonrecovering sensation in CFS are not expressed by sleep variables such as the SEI or sleep stage distributions and proportions.
NICE. (2007). Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy); diagnosis and management. August 22, 2007.
http://guidance.nice.org.uk/CG53[Ed. note: These guidelines promote CBT, GET and activity management (a gentle version of GET). Pacing is dismissed as lacking research evidence. The original version of pacing was not discussed and it was therefore not made clear that this is a strategy for managing limited energy levels, not a treatment. It is appropriate as one component in a multidimensional programme, for which there is evidence, though the various trials were ignored and misclassified e.g. under CBT. An RCT supporting the use of the original version of pacing was classified under GET. As a result, it was possible to argue that there is a lack of evidence. The guidelines offer no advice for patients who do not have maladaptive thoughts or behaviours and who cannot increase their activity levels beyond a certain point.]
Schur, E., Afari, N., Goldberg, J., Buchwald, D and Sullivan, PF. Twin analyses of fatigue. Twin Research and Human Genetics, 2007, 10, 5, 729-733.
Twin studies can be useful in elucidating genetic and environmental influences on fatigue and CFS. The goal of this article was to use biometrical structural equation twin modeling to examine genetic and environmental influences on fatigue, and to investigate whether these influences varied by gender. A total of 1042 monozygotic (MZ) twin pairs and 828 dizygotic (DZ) twin pairs who had completed the University of Washington Twin Registry survey were assessed for three fatigue-related variables: prolonged fatigue, chronic fatigue, and CFS. Structural equation twin modeling was used to determine the relative contributions of additive genetic effects, shared environmental effects, and individual-specific environmental effects to the 3 fatigue conditions.
In women, tetrachoric correlations were similar for MZ and DZ pairs for prolonged and chronic fatigue, but not for CFS. In men, however, the correlations for prolonged and chronic fatigue were higher in MZ pairs than in DZ pairs. About half the variance for both prolonged and chronic fatigue in males was due to genetic effects, and half due to individual-specific environmental effects. For females, most variance was due to individual environmental effects.
Schur, EA., Afari, N., Furberg, H., Olarte, M., Goldberg, J., Sullivan, PF and Buchwald, D. Feeling bad in more ways than one: comorbidity patterns of medically unexplained and psy-chiatric conditions. Journal of General Internal Medicine, 2007, 22, 818-821.
Considerable overlap in symptoms and disease comorbidity has been noted among medically unexplained and psychiatric conditions seen in the primary care setting, such as CFS, low back pain, irritable bowel syndrome, chronic tension headache, fibromyalgia (FM), temporomandibular joint disorder, major depression, panic attacks, and post-traumatic stress disorder. The objective was to examine interrelationships among these 9 conditions. Using data from a cross-sectional survey, we described associations and used latent class analysis to investigate complex interrelationships.
Participants were 3,982 twins from the University of Washington Twin Registry. Measures comprised twins self-reported a doctor's diagnosis of the conditions.
Comorbidity among these 9 conditions far exceeded chance expectations; 31 of 36 associations were significant. Latent class analysis yielded a 4-class solution. Class I (2% prevalence) had high frequencies of each of the 9 conditions. Class II (8% prevalence) had high proportions of multiple psychiatric diagnoses. Class III (17% prevalence) participants reported high proportions of depression, low back pain, and headache. Participants in class IV (73% prevalence) were generally healthy. Class I participants had the poorest markers of health status.
These results support theories suggesting that medically unexplained conditions share a common etiology. Understanding patterns of comorbidity can help clinicians care for challenging patients.
[Ed. note: An alternative explanation for the results is that the broad criteria for CFS do not differentiate between similar populations sharing symptoms such as fatigue and headaches. Given the reliance on the presence of 4 ubiquitous symptoms, a statistical association between CFS and the other named disorders is therefore not surprising. Thus it may reflect confounding, not a common aetiology.]
Shevchuk, NA. Possible use of repeated cold stress for reducing fatigue in chronic fatigue syndrome: a hypothesis. Behavioral and Brain Functions, 2007, 3:55 [Epub ahead of print]. doi:10.1186/1744-9081-3-55.
Hypothesis paper. Physiological fatigue can be defined as a reduction in the force output and/or energy-generating capacity of skeletal muscle after exertion, which may manifest itself as an inability to continue exercise or usual activities at the same intensity. A typical example of a fatigue-related disorder is CFS, a disabling condition of unknown etiology and with uncertain therapeutic options. Recent advances in elucidating pathophysiology of this disorder revealed hypofunction of the HPA-axis and that fatigue in CFS patients appears to be associated with reduced motor neurotransmission in the central nervous system (CNS) and to a smaller extent with increased fatigability of skeletal muscle. There is also some limited evidence that CFS patients may have excessive serotonergic activity in the brain and low opioid tone.
This work hypothesizes that repeated cold stress may reduce fatigue in CFS because brief exposure to cold may transiently reverse some physiological changes associated with
this illness. For example, exposure to cold can activate components of the reticular activating system such as raphe nuclei and locus ceruleus, which can result in activation of behavior and increased capacity of the CNS to recruit motoneurons. Cold stress has also been shown to reduce the level of serotonin in most regions of the brain (except brainstem), which would be consistent with reduced fatigue according to animal models of exercise-related fatigue. Finally, exposure to cold increases metabolic rate and transiently activates the HPA-axis as evidenced by a temporary increase in the plasma levels of adrenocorticotropic hormone, beta-endorphin and a modest increase in cortisol. The increased opioid tone and high metabolic rate could diminish fatigue by reducing muscle pain and accelerating recovery of fatigued muscle, respectively.
To test the hypothesis, a treatment is proposed that consists of adapted cold showers (20 degrees Celsius, 3 minutes, preceded by a 5-minute gradual adaptation to make the procedure more comfortable) used twice daily. If testing supports the proposed hypothesis, this could advance our understanding of the mechanisms of fatigue in CFS.
[Ed. note: This hypothesis is based on a limited view of CFS, emphasizing fatigue. Low cortisol is only found in a subset and probably related to chronic stress, not CFS per se. There is no evidence of note to support the notion of low levels of serotonin.]
Travers, MK and Lawler J. Self within a climate of contention: Experiences of chronic fatigue syndrome. Social Science & Medicine, 2007 Oct 25; [Epub ahead of print].
doi: 10.1016/j.socscimed.2007.09.003.
CFS is a contested condition associated with scepticism and dispute. This qualitative project examines the illness experiences, and specifically the experiences of self, for people affected with CFS living in Australia.
Using grounded theory methods, theory related to the process of self-renewal and adaptation associated with CFS is explicated. Narratives were derived from semi-structured interviews with 19 adults, including 3 people recovered from CFS. Analysis generated the narrative of the struggling self seeking renewal that defined the illness experience of CFS.
The struggling self articulated the negative effects to self and personhood associated with CFS, defined as the violation of self, and the consequent efforts of participants to manage symptoms and decrease their violation by use of what was termed the Guardian Response and the Reconstructing Response. The Guardian Response provided protection and self-reclamation. The Reconstructing Response fostered self-renewal and meaning.
The struggling self occurred within a climate of threats, and it was these threats which provided the catalyst for violation and the responses. Under different conditions the relative strengths of violation, guardianship or reconstruction fluctuated, and it was these fluctuations that presented the participants with the ongoing struggle of CFS.
Van Den Eede, F., Moorkens, G., Hulstijn, W., Van Houdenhove, B., Cosyns, P., Sabbe, BGC and Claes, SJ. Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome. Psychological Medicine, 2007 Sep 6;1-11 [Epub ahead of print].
doi:10.1017/S0033291707001444.
Studies of HPA axis function in CFS point to hypofunction, although there are negative reports. Suggested mechanisms include a reduced hypothalamic or supra-hypothalamic stimulus to the HPA axis and enhanced sensitivity to the negative feedback of glucocorticoids. The aim of the current study was to investigate HPA axis function in CFS with the dexamethasone/corticotropin-releasing factor (Dex/CRF) test, in analogy with research in affective disorders.
Thirty-four well-characterized female CFS patients (CDC criteria ’94) and 25 healthy control subjects participated in the low-dose Dex/CRF test. Current major depressive episode was an exclusion criterion. However, some were diagnosed with anxiety disorders. History of early-life stress (ELS) was assessed with the Structured Trauma Interview. 21 (61%) were taking benzodiazepines.
Salivary cortisol responses after 0.5 mg Dex were lower in CFS patients than in controls (before 100 mμg CRF, p=0.038; after 100 mμg CRF, p=0.015). A secondary analysis revealed an influence of early-life stress and of oestrogen intake. After removal of the 10 participants who were taking an oral oestrogen, patients without a history of ELS showed lower cortisol responses than patients with ELS and controls (before CRF, p=0.005; after CRF, p=0.008).
CFS is globally associated with reduced cortisol responses in the combined low-dose Dex/CRF test, but this effect is only clearly present in CFS patients without a history of ELS. This study provides further support for an enhanced glucocorticoid negative feedback and/or a reduced central HPA axis drive in CFS. Furthermore, it demonstrates that ELS is an important variable to consider in CFS research.
[Ed. Note: The inclusion of patients with anxiety disorders could have confounded the results, given that the HPA axis is influenced by current levels of stress. Comparison with a medically-ill control group may have provided information on the association between cortisol and being unwell. It is interesting that the benzodiazepines did not affect the results.]
Ismail, K., Kent, K., Sherwood, R., Hull, L., Seed, P., David, AS and Wessely S. Chronic fatigue syndrome and related disorders in UK veterans of the Gulf War 1990-1991: results from a two-phase cohort study. Psychological Medicine, 2007 Sep 25:1-9 [Epub ahead of print]. doi:10.1017/S0033291707001560.
The aim was to determine the prevalence of CFS (CDC criteria ’94), chronic fatigue and FM in UK military personnel after the Gulf War 1990-1991.
A two-phase cohort study was used. Three randomly selected subsamples identified from a population-based cross-sectional postal survey of over 10 000 current and ex-service UK military personnel (Gulf veterans were those deployed to the Gulf War 1990-1991; non-Gulf veterans were Bosnia peacekeepers 1992-1997 and those on active duty during the Gulf War 1990-1991 but not deployed) were recruited. Their disability status was assessed using the Short Form 36 physical functioning scale; Gulf veterans who reported physical disability (n=111) were compared with non-Gulf (n=133) veterans who reported similar levels of physical disability. Screening for known medical and psychiatric conditions was conducted to exclude medical explanations for disability and symptomatic distress. Standardised criteria for CFS, chronic fatigue and FM were used.
Disabled Gulf veterans were more likely to be overweight, have elevated gamma-glutamyl transferase levels and screen positive for hypertension. There were no other clinically significant differences in clinical markers for medically explainable conditions. Disabled Gulf veterans were more likely than similarly disabled Bosnia and Era veterans (adjusted odds ratio 7.8, 95% confidence interval 2.5-24.5) to meet the criteria for CFS. Rates for other medically unexplained conditions were not significantly increased.
Symptoms in keeping with CFS account for a significant part of the symptomatic distress in Gulf veterans.
Deary, V., Chalder, T and Sharpe, M. The cognitive behavioural model of medically unexplained symptoms: A theoretical and empirical review. Clinical Psychology Review, 2007, 27, 7, 781-797.
The article is a narrative review of the theoretical standing and empirical evidence for the cognitive behavioural model of medically unexplained symptoms (MUS) in general and for CFS and irritable bowel syndrome (IBS) in particular. A literature search of Medline and Psychinfo from 1966 to the present day was conducted using MUS and related terms as search terms. All relevant articles were reviewed. The search was then limited in stages, by cognitive behavioural therapy (CBT), condition, treatment and type of trial.
Evidence was found for genetic, neurological, psychophysiological, immunological, personality, attentional, attributional, affective, behavioural, social and inter-personal factors in the onset and maintenance of MUS. The evidence for the contribution of individual factors, and their autopoietic interaction in MUS (as hypothesised by the cognitive behavioural model) is examined. The evidence from the treatment trials of cognitive behavioural therapy for MUS, CFS and IBS is reviewed as an experimental test of the cognitive behavioural models. We conclude that a broadly conceptualized cognitive behavioural model of MUS suggests a novel and plausible mechanism of symptom generation and has heuristic value. We offer suggestions for further research.
Extracts: “The sine qua non of any CBT model is a vicious circle, the hypothesis that a self perpetuating interaction between different domains maintains symptoms, distress and disability...” Rygh et al. (2005) suggested that central mechanisms such as vigilance and attention, or the effects of anxiety, depression or stress, may dampen inhibition of these pathways, lowering the threshold yet further. This could lead to normally benign sensations being experienced as pain, leading in turn to further sensitisation and vigilance... Rief and Barsky (2005) acknowledged Dantzer's research but noted that whilst there is some evidence that immune changes can induce behaviour change, it is “unclear whether this causality can also be bi-directional and whether it contributes especially to the development and maintenance of somatoform symptoms in humans.” They observed that the biological findings in patients with MUS are highly varied and do not yet present a consistent and coherent picture. Whilst there is some evidence of increased autonomic arousal and of delayed recovery of the stress response, these findings vary between conditions and between different phases of the same condition. Therefore rather than anchor their explanation to a particular bodily system, Rief and Barsky (2005) proposed a more generic model in which symptoms arise through a two stage process of generation and selection. At the first stage, bodily symptoms may be generated by multiple determinants including over-arousal, chronic stressors, HPA activity, sensitisation etc. At the second stage a hypothetical filter system selects symptoms for conscious attention. This selective process will in turn have multiple determinants: health anxiety, depression, lack of distraction, uncertainty as to origin of symptom etc. These contribute to “faulty filtering” and increased symptom perception. Brown (2004) has suggested a similar model which emphasises the roles of attention, mis-attribution and mis-interpretation in the maintenance of MUS... A cognitive bias develops for symptoms, further amplifying them which serves to further sensitise “the neural loops supporting cognitive rumination… pain and illness lead to more pain and illness” (Ursin, 2005).
“These models are notably similar to Barsky and Borus's (1999) somatosensory amplification and Rief and Nanke's (1999) cognitive-psychobiological framework...” On the model itself: “An innate tendency to somatopsychic distress and ease of distress sensitisation, combined with childhood adversity, increase both the amount of symptoms experienced and lowers the threshold for their detection. Life events and stress lead to physiological changes which produce more symptoms and set up processes of sensitisation and selective attention. This further reduces the threshold of symptom detection. Lack of explanation or advice increases anxiety, symptoms and symptom focus. Stress cues become associated with symptoms through classical conditioning. Avoidance of symptom provocation, and symptom-led activity patterns, lead to further sensitisation through operant conditioning. The prolonged stress of the illness experience itself further activates physiological mechanisms, producing more symptoms, sensitisation, selective attention and avoidance. The individual can thereby become locked into a vicious cycle of symptom maintenance... The CBT model of CFS (see Suraway et al., 1995; Deary & Chalder, 2006) hypothesises that in vulnerable individuals, such as those who are over-active or under stress, CFS is precipitated by life events or viruses leading to an autopoietic cycle in which physiological changes, illness beliefs, reduced and inconsistent activity, sleep disturbance, distress, medical uncertainty and lack of guidance interact to maintain symptoms. The evidence supports some of the individual dots in this picture but not yet the lines between them...
The nature of individual differences in susceptibility to MUS would also merit further attention. High neuroticism may offer an underlying common mechanism for distress sensitivity and intolerance which lowers the threshold for symptom detection (both mental and physical), and leads to increased propensity to conditioned responses, more attention to threat stimuli and more avoidant coping. The neuroticism concept captures many of the factors hypothesised to be at work in MUS. This would suggest two further lines of research. Firstly, more examination of the physiological, cognitive and behavioural markers of N [neuroticism] might give us more insight into the processes at work in MUS. Secondly, longitudinal studies in N might give us a clearer idea of what mediates and moderates development of MUS in vulnerable individuals. The CBT model of MUS offers a previously undescribed illness mechanism maintaining a distinct group of disorders that we might call autopoietic conditions. The fundamental hypothesis underlying the model is that symptoms are maintained by a self perpetuating, multi-factorial cycle. Treatment is aimed at elaborating the unique inter-play of factors in any given patient and dismantling the autopoietic mechanism by making changes in target areas... Distress intolerance is a key theme in the CBT model of MUS maintenance. Symptoms are perceived as aversive/threatening, which triggers a physiological response, which serves to maintain avoidance, symptom focus and symptoms. One hypothesis would be that developing the ability to tolerate symptoms whilst not letting them dictate behaviour would be a promising line of enquiry. The so called third wave of CBT, particularly Acceptance and Commitment Therapy (see Hayes, Strosahl, &Wilson, 1999), with its emphasis on distress tolerance and goal maintenance would seem well suited as a paradigm to apply to these conditions, as would the related intervention of mindfulness.”
[Ed. note: This review relies on a reductionistic approach, i.e. the view that an illness is not a disease unless it has an identifiable ‘physical’ cause, plus the assumption that if no such cause has been identified in 20 years, there may not be a physical cause to be identified. To put it another way, here absence of evidence is taken as evidence of absence.
Given that the current definition of CFS selects a heterogeneous population, there is unlikely to be a single cause. It is this which has led to inconsistent findings in biomedical research and the uncertainty regarding aetiology which helps to perpetuate the CBT theory. Aside from the ‘lack of a physical cause’ argument, the model also continues to rely on the assumption of the ‘universal response’, which is invariably unhelpful, especially in combination with maladaptive personality traits (e.g. perfectionism, neuroticism). Thus there is no recognition of the research indicating the use of appropriate, adaptive coping strategies (e.g. Saltzstein et al 1998), let alone the fact that many patients engage in pro-active coping such as pacing (original version). Pro-active coping appears to be linked with positive outcomes in the same way that the strategies described in the paper are often associated with negative ones (Aspinwall and Taylor 1997). Furthermore, there is no recognition of individual differences in either the appraisal of threats, or traits such as optimism, hardiness and resilience, and the model cannot explain the outbreaks. (The raised N scores in the chronic phase after the Royal Free outbreak were almost certainly due to the inclusion of somatic items common to both neuroticism and the illness itself. Research has shown that N scores are no different to those found in MS and the research team themselves found that neuroticism was not a predictor of CFS, cf Harvey et al, above).
Also noteworthy is the relegation or downplaying of factors such as immune activation and ongoing infection. These are regarded as “intriguing” but otherwise ignored. This selective attention in analysis of the data again reflects the reductionistic thinking and lack of objectivity on which this model depends.
As well as factors such as maladaptive behaviours and stress, this new version of the CBT model includes the notion of misattribution. As documented before, this assumes that the evidence of ongoing pathology documented in ME and CFS is probably unreliable (e.g. Innes 1970, Lane et al 2003, Natelson et al 2005, Chia and Chia 2007). The approach towards variables such as misattribution is consistent with the discussion of personality (e.g. references to studies where only some participants met the CDC criteria, cf. White and Schweitzer 2000). And as before, there is a notable reliance on generalisations. For example, because one study found that people with IBS engaged in ‘all or nothing’ coping, it does not mean that this strategy is used in the same way by other patient groups, and the authors' reference to a “clinically prevalent belief” that this is the case in relation to CFS is anecdotal. Interestingly, this is exactly the kind of evidence the same team reject when offered by those outside the CBT school, e.g. in support of strategies such as pacing.
This is admittedly a more sophisticated model than the previous version but it still does not explain some of the neurological signs documented in ME, nor the abnormalities found in other subsets. Raised levels of cytokines are linked to low cortisol and ‘burn-out’, but not to the evidence of ongoing infection (cf. Lane et al 2003, Chia and Chia 2007). However, an objective observer must acknowledge the inconsistent ‘physical’ findings relating to CFS, hence it is fruitful to focus a little more on the weakness or strength of the psychological arguments.
The carefully linked associations between different components of the model are elegant and seemingly persuasive unless the reader is familiar with the literature and is aware, for instance, the fact that some of the cited references are speculative reviews (e.g. Barsky and Borus, Henningsen et al 2003) rather than reports of original research. The emphasis on sensitisation and attention reflects a bias, as does the lack of weight given to the evidence of ongoing pathology. Overall, the speculation about attention and sensitisation reinforces the CBT’s school’s tendency to trivialise the symptoms, and given the actual paucity of evidence, the authors overstate the significance of psychological factors such as ‘faulty filtering’, hyper-reflection, maladaptive coping and attributions. Models such as Lazarus’s theory of stress and coping, which recognise individual differences, are ignored, as is research suggesting that most patients appear to have realistic attributions. Indeed, members of the CBT school themselves have found psycho-social attributions in their own studies. Are these also unhelpful?
One question which was not answered here, nor in the previous version, is how a virus might trigger the illness, but attention, beliefs and low cortisol suddenly cause the exact same symptoms after the virus has gone. The assumption that patients cannot tell when the disease has passed and psychological factors have taken over, requires evidence of a personality trait which does not recognise significant differences in internal cues. These patients therefore would also not be able to recognise when influenza has passed and they are ‘on the mend’. I am not aware that such evidence exists. Alternative explanations for the alleged responses include an abnormally low IQ, plus a history of exaggerating symptoms and high levels of sick leave. Research does not support either of these arguments.
Similarly, the model fails to explain the documented exacerbation of symptoms 24 hours to five days following activity, as indicated by researchers using objective measures. There is also sound evidence in patients with ME that the muscles are weak, and consequently, that the symptoms are not merely a reflection of an (unfounded) fear of exacerbations, cf Paul et al 1999. It is also hard to attribute fatigue after five days to deconditioning.
While the new model recognises the complexity of CFS to a far greater degree than the first, I remain unconvinced. It appears to have the subtext: patients are not to be believed, they misunderstand and exaggerate. This brings us back to the explanations of psychiatrists such as McEvedy and Beard and Barsky and Borus. They all showed a tendency to misogyny, portraying patients as generally female, stupid, gullible and without sense. Though the authors cite a person questioning the direction of causality, the rest of the paper leaves readers with the clear message that all the associations are invariably one way. Thus the psychological mechanisms cause the immunological and HPA abnormalities, the anxiety and depression reflect the “distress proneness”, and so on. References to support the apparently universal use of avoidance coping are missing, possibly because avoidance behaviour in CFS tends to be limited (cf Sisto et al 1998). The vicious circle model predicts that the symptoms would get progressively worse but in most patients with CFS, they do not. This, as so many other aspects of CFS, receives little attention, as do other ‘inconvenient truths.’ The model also fails to address which component might explain the improvements noted in a significant proportion of patients over time. Do people suddenly become less perfectionist? Do they become less sensitive to stress? The natural course of the condition is not discussed, and therefore requires no explanation. This too is part of the modus operandi of the CBT school, (they never discuss findings such as McGarry et al 1994 and Paul et al 1999 for the same reason), and the new, more complex model, merely continues where the old, discarded one, left off.
Other means of diverting attention and avoiding difficult questions involves recategorising findings. The Wallman et al paper on pacing is classed as a study of GET even though the protocol permitted patients to stop the activity if they felt unwell. This is contrary to the ‘no pain, no gain’ principle behind GET, where patients are encouraged to continue and tolerate symptoms as long as they can. However, I welcome the acknowledgement that the treatment effects associated with CBT are “modest at best” (p.9) and the acceptance that the links between the various components are far from solid. But the main impression of this paper is one of missing information and bias. The lack of measures of immune function etc are not mentioned as factors which may have confounded results. This subjective approach reflects a lack of respect for the scientific process, e.g. recognising findings which do not support the model, discussing the evidence for alternative views and most of all, an accurate discussion of the experiences and views of those who suffer from the conditions. These criticisms do not preclude the possibility that there is a subset of patients within the CFS population whose symptoms are perpetuated largely by fear etc, and I accept that some patients may believe the misinformation on the internet and subsequently develop maladaptive beliefs, adding to the stress and undermining the HPA axis etc as a result.
I wish to encourage a greater tolerance of alternative views and more objectivity. I believe that these are essential to help us understand the aetiology of CFS and to improve the standard of patient care. The scientific process depends on the availability of a range of opinions, and this motivated this commentary. Please note that the above criticisms relate to specific arguments, and do not reflect a personal preference for another model dealing with aetiology.]
Ellen Goudsmit PhD. Independent Health Psychologist.
Kennedy, P. (Ed.) Psychological Management of Physical Disabilities. A Practitioner’s Guide. Hove: Routledge; 2007. Pb £24.99
This excellent and well-written book doesn’t include information on CFS but covers the management of several chronic (medical) diseases and provides up-to-date information on the most interesting theories and helpful interventions. There are alternatives to CBT and this guide offers a timely review.
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