Number 2 |
1st June 2005 |
IMMUNOLOGY
|
Tomoda, A., Joudoi, T., Rabab, E-M, Matsumoto, T., Park, TH and Miike, T. Cytokine production and modulation: Comparison of patients with chronic fatigue syndrome and normal controls. Psychiatry Research, 2005, 134, 1, 101-104.
We studied cytokine production in 15 patients with CFS (CDC criteria ’94) and 23 controls. CFS patients' peripheral blood mononuclear cells were cultured with lipopolysaccharide or phytohemagglutinin.
Enzymatic immunoassay indicated cytokine concentration in culture supernatants. CFS patients showed significantly lower mRNA levels and transforming growth factor-ß (TGF-ß1) production (in vitro). This was the only abnormality found.
Cytokine dysregulation affects CFS pathogenesis. TGF-ß1 may aid treatment because it affects CFS inflammatory characteristics.
Jammes, Y., Steinberg, JG., Mambrini, O., Bregeon, F and Delliaux, S. Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. Journal of Internal Medicine, 2005, 257, 3, 299-310.
Because the muscle response to incremental exercise is not well documented in patients suffering from CFS, we combined electro-physiological (compound-evoked muscle action potential, M wave), and biochemical (lactic acid production, oxidative stress) measurements to assess any muscle dysfunction in response to a routine cycling exercise.
This case-control study compared 15 CFS patients (CDC criteria ’94) to a gender-, age- and weight-matched control group (n=11) of healthy, sedentary subjects. All subjects performed an incremental cycling exercise continued until exhaustion. Outcome measures included oxygen uptake (VO2), heart rate (HR), systemic blood pressure, percutaneous O2 saturation (SpO2), M-wave recording from vastus lateralis, and venous blood sampling allowing measurements of pH (pHv), PO2 (PvO2), lactic acid (LA), and three markers of the oxidative stress (thiobarbituric acid-reactive substances, TBARS, reduced glutathione, GSH, and ascorbic acid, RAA).
In CFS patients, the slope of VO2 versus work load relationship did not differ from control subjects and there was a tendency for an accentuated PvO2 fall at the same exercise intensity, indicating an increased oxygen uptake by the exercising muscles. Compared to controls:
- the HR and blood pressure responses to exercise did not vary;
- the anaerobic pathways were not accentuated;
- the exercise-induced oxidative stress was enhanced with early changes in TBARS and RAA and - enhanced maximal RAA consumption;
- and the M-wave duration markedly increased during the recovery period. 11 of the 15 patients did not report significant post-exertional fatigue or an exacerbation of symptoms.
The response of CFS patients to incremental exercise associates a lengthened and accentuated oxidative stress together with marked alterations of the muscle membrane excitability. These two objective signs of muscle dysfunction are sufficient to explain muscle pain and post-exertional malaise reported by our patients.
Snell, CR., Vanness, JM., Strayer, DR and Stevens, SR. Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS). In Vivo, 2005, 19, 2, 387-390.
Hyperactivition of an unwanted cellular cascade by the immune-related protein RNase L has been linked to reduced exercise capacity in persons with CFS. This investigation compares exercise capacities of CFS patients with deregulation of the RNase L pathway and CFS patients with normal regulation, while controlling for potentially confounding gender effects.
Thirty-five male and seventy-one female CFS patients performed graded exercise tests to voluntary exhaustion. Measures of peak VO2, peak heart rate, body mass index, perceived exertion, and respiratory quotient were entered into a two-way factorial analysis with gender and immune status as independent variables.
A significant multivariate main effect was found for immune status (p< 0.01), with no gender effect or interaction. Follow-up analyses identified VO2(peak) as contributing most to the difference.
These results implicate abnormal immune activity in the pathology of exercise intolerance in CFS and are consistent with a channelopathy involving oxidative stress and nitric oxide-related toxicity.
Whistler, T., Jones, JF., Unger, ER and Vernon, SD. Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects. BMC Physiology, 2005, Mar 24; 5, 1, 5.
CFS is defined by debilitating fatigue that is exacerbated by physical or mental exertion. To search for markers of CFS-associated post-exertional fatigue, we measured peripheral blood gene expression profiles of women with CFS and matched controls before and after exercise challenge.
Five women with CFS (CDC criteria ’94, no allergies) and 5 healthy, age-matched, sedentary controls were exercised on a stationary bicycle at 70% of their predicted maximum workload (20 minutes). Blood was obtained before and 24 hours after the challenge, total RNA was extracted from mononuclear cells, and signal intensity of the labeled cDNA hybridized to a 3800-gene oligonucleotide microarray was measured. We identified differences in gene expression among and between subject groups before and after exercise challenge, and evaluated differences in terms of Gene Ontology categories.
Exercise-responsive genes differed between CFS cases and controls. These were in genes classified in chromatin and nucleosome assembly, cytoplasmic vesicles, membrane transport, and G protein-coupled receptor ontologies. Differences in ion transport activity/ion channel activity were evident at baseline and were exaggerated after exercise as evidenced by greater numbers of differentially genes in these molecular functions.
These results highlight the potential use of an exercise challenge combined with microarray gene expression analysis in identifying gene ontologies associated with CFS.
The complete article is available in PDF format at:
http://www.biomedcentral.com/content/pdf/1472-6793-5-5.pdf
[These findings are consistent with other studies showing abnormal responses to exercise e.g. McCully and Natelson 1999 (oxidative metabolism), Paul et al 1999 (muscle power), Sorensen et al 2003 (immune system), and Whiteside et al 2004 (change in pain threshold following GET). This plus Black et al 2005 (below) conflicts with the view that increasing activity levels as promoted in the CBT model is theoretically sound, effective and has no adverse effects.]
Inder, WJ., Prickett, TC and Mulder, RT. Normal opioid tone and hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome despite marked functional impairment. Clinical Endocrinology (Oxf), 2005, 62, 3, 343-348.
The aim of this study was to determine whether the functional impairment seen in CFS is associated with reduced levels of central opioids and/or deficiency of the hypothalamic-pituitary-adrenal (HPA) axis. This was a single-blinded case-control study measuring functional and psychological status, basal hormonal parameters and the ACTH/cortisol response to naloxone and ovine corticotrophin-releasing hormone (oCRH) vs. placebo in people with CFS and healthy controls.
Twelve people with CFS (CDC criteria ’94, no MD) were compared to 11 age-matched controls. Measurements included hormonal parameters: basal levels of 09:00 h plasma cortisol, dehydroepiandrosterone sulfate (DHEAS) and IGF-1, 24-h urinary free cortisol, plasma ACTH and cortisol response to naloxone 125 microg/kg, oCRH 1 microg/kg and placebo (normal saline). Psychological parameters included SF-36, Hamilton Depression Score, Hospital Anxiety and Depression Scale and Fatigue Scale. Four patients were taking oral oestrogen, as were 2 controls.
There were highly significant differences between the CFS subjects and the controls with respect to the measures of fatigue and physical functioning. (Mean PF score of the patients was 55). However, there were no differences in basal levels of 09:00 h cortisol (367 vs. 331 nmol/l, p=0.51), DHEAS (4.2 vs. 4.0 micromol/l, p=0.81), 24-h urinary free cortisol (182 vs. 178 nmol/24 h, p= 0.91) or IGF-1 (145 vs. 130 microg/l, p=0.52) between the CFS group and controls, respectively. There was also no difference between the groups with respect to the ACTH and cortisol response to either oCRH or naloxone.
Conclusions: Our data do not support an aetiological role for deficiency in central opioids or the HPA axis in the symptoms of CFS
[Ed. Note: There are no data for the duration of illness or stress at the time of testing. The raised levels of anxiety (HAD) suggests this may have led to slightly raised levels of morning cortisol.]
Segal, TY., Hindmarsh, PC and Viner RM. Disturbed adrenal function in adolescents with chronic fatigue syndrome. Journal of Pediatric Endocrinology and Metabolism, 2005, 18, 3, 295-301.
The aim of this study was to investigate adrenal function in children and adolescents with CFS compared with age-matched controls. Low dose (500 ng/m2) synacthen tests (LDST) were completed in 23 adolescents with CFS and 17 age-matched controls. Serum cortisol concentrations were measured at 5-min intervals from 10 to 45 minutes. Peak serum cortisol concentration, time to peak, rise in cortisol and area under the curve (AUC) were derived.
Patients with CFS had significantly lower mean cortisol levels during the LDST (p <0.001), lower peak cortisol (p <0.025), reduced cortisol AUC (p <0.005) and longer time to peak cortisol (p <0.05). Abnormalities were seen in both sexes but were more pronounced in females. Unstimulated adrenal androgen and 17-hydroxyprogesterone concentrations were normal.
Adolescents with CFS have subtle alterations in adrenal function suggesting a reduction in central stimulation of the adrenal glands. The more pronounced effects in females may reflect differential central effects of stress on HPA axis regulation between the sexes.
Rangel, L., Garralda, ME., Jeffs, J and Rose, G. Family health and characteristics in chronic fatigue syndrome, juvenile rheumatoid arthritis, and emotional disorders of childhood. Journal of the American Academy of Child & Adolescent Psychiatry, 2005, 44, 2, 150-158.
This study compared family health and characteristics in children with CFS, in juvenile rheumatoid arthritis (JRA), and emotional disorders.
Parents of 28 children and adolescents aged 11 to 18 years with CFS, 30 with JRA, and 27 with emotional disorders (i.e., anxiety and/or depressive disorders) were recruited from specialty clinical settings and completed interviews and questionnaires assessing family health problems, parental mental distress, illness attitudes, and family burden of illness.
Parents of children with CFS were significantly more likely than those of children with JRA to report a history of CFS-like illness, high levels of mental distress, and a tendency to experience functional impairment in response to physical symptoms. Families of children with CFS were characterized by significantly greater emotional involvement and reported greater family burden related to the child's illness in comparison with families of children with JRA.
CFS in childhood and adolescence is associated with higher levels of parental CFS-like illness, mental distress, emotional involvement, and family illness burden than those observed in association with JRA, a chronic pediatric physical illness.
Schoofs, N., Bambini, D., Ronning, P., Bielak, E and Woehl, J. Death of a lifestyle: The effects of social support and healthcare support on the quality of life of persons with fibromyalgia and/or chronic fatigue syndrome. Orthopaedic Nursing, 2004, 23, 6, 364-374.
The purpose of this study was to investigate how social support and healthcare support affect the quality of life of persons with fibromyalgia (FMS) and CFS.
A constant comparison method was used for the qualitative portion of the research and descriptive correlational methods were used for the quantitative portion. This mixed design research study suggested that social support, unlike healthcare support, is related to Quality of Life (QOL). It was also evident that subjects suffering from CFS and/or FMS do not experience high levels of social support.
Black, CD., O'Connnor, PJ and McCully, KK. Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome. Dynamic Medicine, 2005, 4, 3.
Individuals with CFS have been shown to have reduced activity levels associated with heightened feelings of fatigue. Previous research has demonstrated that exercise training has beneficial effects on fatigue-related symptoms in individuals with CFS. The aim of this study was to sustain an increase in daily physical activity in CFS patients of around 30% over 4 weeks and assess the effects on fatigue, muscle pain and overall mood.
Six physician-diagnosed CFS patients (all reporting post-exertional fatigue, none with a history of psychiatric disorder, 5 also had FM) and seven sedentary controls were studied. Daily activity was assessed by a CSA accelerometer worn on a belt around the waist. Following a two week baseline period, CFS subjects were asked to increase their daily physical activity by 30% over baseline by walking a prescribed amount each day for a period of four weeks. Fatigue, muscle pain and overall mood were reported daily using a 0 to 100 visual analogue scale and weekly using the Profile of Mood States (Bipolar) questionnaire.
CFS patients had significantly lower daily activity counts than controls during a 2-week baseline period (p=.017). At baseline, the CFS patients reported significantly (p<0.01) higher fatigue and muscle pain intensity compared to controls but the groups did not differ in overall mood. CFS subjects increased their daily activity by 28 +19.7% over a 4 week period (range 13-60%). Four did not reach the 30% goal. No adverse events were reported. However, overall mood and muscle pain worsened in the CFS patients with increased activity. There was also an increase in fatigue but this was not significant. The POMS revealed significant group differences on the fatigue and vigor subscales and these did not change over time as activity increased. There was no changes documented in the controls.
CFS patients were able to increase their daily physical activity for a period of four weeks. In contrast to previous studies fatigue, muscle pain, and overall mood did not improve with increased activity. Increased activity was not presented as a treatment which may account for the differential findings between this and previous studies. The results suggest that a daily "activity limit" may exist in this population. Future studies on the impact of physical activity on the symptoms of CFS patients are needed.
[Note: The full text is available for free in PDF format at:
http://www.dynamic-med.com/content/pdf/1476-5918-4-3.pdf .]
Moss-Morris, R., Sharon, C., Tobin, R and Baldi, JC. Randomized controlled graded exercise trial for chronic fatigue syndrome: outcomes and mechanisms of change. Journal of Health Psychology, 2005, 10, 2, 245-259.
The aim of this study was to investigate the potential mechanisms underlying the efficacy of graded exercise therapy for CFS. Forty-nine patients with CFS (CDC criteria ’94) were randomized to a 12-week graded exercise programme or to standard medical care. At the end of treatment, the exercise group rated themselves as significantly more improved and less fatigued than the control group. A decrease in symptom focusing rather than an increase in fitness mediated the treatment effect. Graded exercise appears to be an effective treatment for CFS and it operates in part by reducing the degree to which patients focus on their symptoms.
[Ed. Note: There were 25 patients in the treatment arm and 24 in the controls. Exercise was gentle and the aim initially was to reach 40% of VO2 max on the treadmill test to be maintained for 10-15 minutes, 4 to 5 times a week. Initial targets were set at a level unlikely to exacerbate symptoms. Consistency was emphasized. There were weekly meetings to assess progress and set new goals. Intensity was increased after six weeks, before that, only duration was increased. The final goal was to exercise for 30 minutes, 5 days a week at 70% of VO2 max. The only symptoms assessed were fatigue, anxiety and depression.
12% dropped out (3 from treatment though not because of relapses, 3 from controls). At baseline, the controls had been ill longer (median 5 years versus 2.67 in the treatment arm). They also had lower scores for physical functioning indicating greater impairment (45.65 versus 53.10). At the end of treatment, the score was 69, still below normal. 54.5% reported that they had ‘improved’, compared to 23.8% of controls and after intention-to-treat analysis, 48% rated themselves as better or very much better compared to 21% of controls. At six months, the group difference for physical fatigue remained (p<.05) with 54% rating themselves ‘better’ or ‘very much better’ after treatment versus 28% of the controls. There was no significant group difference for mental fatigue or physical functioning. There was no additional improvement. There was a slight decrease in symptom focusing.
13% had scores on the HAD suggesting significant anxiety and 13% had significant depression. A total of around 40% had some kind of probable anxiety or depressive disorder. There was also an increase in heart rate in the exercise group, which was unexpected. There was a trend suggesting that patients who changed their perceptions about a number of symptoms also decreased their fatigue scores and rated themselves as significantly better after treatment. An increase in fitness was not significantly related to an improvement in physical and mental fatigue but there was a link with heart rate. The heart rate monitor was used to assess if exercise was safe or not. At the end of treatment, 68% of the patients rated the therapy as ‘effective’ or ‘highly effective’ and the same number rated it as ’better’ or ‘very much better’ than any other treatment they had received to date. According to the authors, this study adds to the body of evidence showing that graded activity is an “effective treatment for CFS” though given there is little data on neurological or immunological symptoms, this is speculative rather than evidence-based.]
Wright, B., Ashby, B., Beverley, D., Calvert, E., Jordan, J., Miles, J., Russell, I and Williams, C. A feasibility study comparing two treatment approaches for chronic fatigue syndrome in adolescents. Archives of Disease in Childhood, 2005, 90, 369-372
There is lack of consensus about the effectiveness of the main treatment approaches for CFS. These range from approaches that involve high levels of rest, through "pacing" to more active rehabilitation. More active rehabilitation has developed as a treatment focusing on graded rehabilitation, and more recently cognitive behavioural techniques. They are now more likely to integrate a range of approaches to address physiological, psychological, social, and systemic aspects of the syndrome.
This study assesses the feasibility of a larger treatment trial comparing the effectiveness of the two current most common treatment approaches. We sought to explore the acceptability of treatments and the numbers needed to show a meaningful difference between treatments.
Young patients meeting the Oxford criteria for CFS (using the recommended modification for children of three months' fatigue) were given further information about the study. Participants were randomised to one of two treatment groups using remote randomisation at York University Over one year, clinic appointments were weekly for one month, 2 weekly for the next three months, 3 weekly for two months, and 4 weekly for six months. Three clinicians (BW, CW, BA) conducted both treatment options using treatment manuals. The paediatrician (DWB) saw all young people every 12 weeks. Both treatment arms included: a strong emphasis on collaboration with patient and family; support and advice to establish a normal eating pattern, a balanced healthy diet and healthy sleep patterns.
"Pacing" is described in a document presented to the Chief Medical Officer's working group on CFS/ME and included: (1) pacing activity to the changing needs and responses of the body by exercising to the point of tolerance, avoiding overexertion; (2) managing energy within an overall limit ("glass ceiling"); (3) resting when necessary, but avoiding total rest; (4) avoiding physiccally and/or emotionally stressful situations until ready; and (5) tailoring return to school to the needs of the young person, taking careful heed of symptoms, the child, and the family.
The STAIRway to Health programme involved a Structured TAilored Incremental Rehabilitation programme. This incorporated some aspects of previously researched approaches. In particular, time was spent providing a holistic understanding of CFS that moved away from an exclusively physical or an exclusively psychological understanding of the illness, explaining vicious cycles that exacerbate illness, including physical deconditioning, social isolation, and emotional cycles (including loss of self-esteem and confidence), bolstering adaptive coping strategies and reevaluating negative attributions about the illness and the future.
Fourteen young people had newly diagnosed CFS; one declined. Thirteen (age range 8.9-16.9 years) gave informed consent. They were all in mainstream schools and were incapacitated by CFS to the point of not being able to attend. Six had been unwell for less than 1 year. Six were in the pacing arm, seven in the STAIRway arm.
At the end of the study 100% of children in the STAIRway to Health arm showed completely healthy scores for all activity up to and including moderate exertional activities. No child had any problems with bike riding, swimming, and similar activities. In the pacing arm, 60% had problems in all three of these activities and still had some difficulties getting around school, compared with no problems in the STAIRway arm. Forty per cent in the pacing group still had problems with bending and lifting.
The pacing programme showed little improvement in activity scores rated by child or clinician and a deterioration in school attendance, whereas activity and school attendance were improved markedly in the STAIRway to health arm. Global health improved in both arms although more in the STAIRway arm than the pacing arm whether measured by child or clinician.
[Ed. Note: There were some notable differences at baseline between the groups e.g. more fatigue and anxiety and lower physical activity scores in the STAIRway arm. The version of pacing described in the CMO’s report bears little resemblance to that advocated by Goudsmit. Goudsmit and Jason both regard pacing as one component of a programme and do not advocate that it be used on its own. The lack of attention focused on other aspects of the illness experience may explain the disappointing results.]
Cairns, R and Hotopf, M. A systematic review describing the prognosis of chronic fatigue syndrome. Occupational Medicine, 2005 55, 1, 20-31.
[Ed. Note: This and three other reviews from King’s College Hospital, London, discuss CFS from the perspective of the CBT model, e.g. with references to ‘excessive rest’ and to the association between attribution and poor outcome, without noting the evidence to the contrary. Some reviews include factual errors. The lack of objectivity means the discussion of findings is selective.]
Cho, HJ., Hotopf, M and Wessely, S. The placebo response in the treatment of chronic fatigue syndrome: a systematic review and meta-analysis. Psychosomatic Medicine, 2005, 67, 301-313.
A review of trials indicated that the pooled placebo response in this patient population is low (19.6%) which is lower than that found in other medical conditions. The response for infectious- immunological or complementary interventions was higher.
[Ed. Note: the authors posit that the low placebo response for psychiatric interventions may be linked to the patients’ expectations. However, one study of an intervention featuring explanation, advice, counselling and antidepressants when required appeared to have a comparatively high placebo-response (50% of the waiting-list controlled reported an improvement). This suggests that perhaps patients reject the CBT model promoted in most of the psychiatric programmes, but are open to approaches with less simplistic explanations. It also alludes to a second influence, namely the fluctuating nature of ME. This means that at any given moment, a number of patients will be feeling better, irrespective of treatment. This makes it difficult to assess the true placebo effect. Reference 78 is inaccurate, as it is a combination of the title of the study and thesis. That study probably met the inclusion criteria but was excluded.]
Glozier, N. Chronic fatigue syndrome: it’s tiring not knowing much - an in-depth review for occupational health professionals. Occupational Medicine, 2005, 55, 1, 10-12.
Jason, LA., Corradi, K., Torres-Harding, S., Taylor, RR and King, C. Chronic fatigue syndrome: the need for subtypes. Neuropsychology Review, 2005, 15, 1, 29-58.
[This discusses fundamental issues relating to diagnosis, treatment and research.]
Ranjith, G. Epidemiology of chronic fatigue syndrome. Occupational Medicine, 2005, 55, 1, 13-19.
Rimes, KA and Chalder, T. Treatments for chronic fatigue syndrome. Occupational Medicine, 2005, 55, 1, 32-39.
Berger, E. Brain imaging in fatigue syndromes. Journal of the Royal Society of Medicine, 2005, 98, 135.
This letter responds to a paper by Gallagher et al (ibid 2004, 97, 571). It notes that recent developments in functional MRI have pointed to a more scientific approach in diagnosing conditions referred to as ‘fatigue syndromes’.
Bowen, J., Pheby, D., Charlett, A and McNulty, C. Chronic Fatigue Syndrome: a survey of GPs' attitudes and knowledge. Family Practice, 2005, online April 1st.
GPs need evidence and guidance to help them diagnose and manage CFS appropriately. The aim of this survey was to obtain baseline data and identify the factors associated with GPs' attitudes to and knowledge of CFS/ME. The attitude of GPs to the condition is an important indicator of likely prognosis.
A postal questionnaire was sent to 1054 GPs served by Taunton, Bristol and Gloucester laboratories. GPs' attitudes to nine statements about CFS/ME were assessed and the factors associated with positive or negative responses were determined. Knowledge of the clinical features was also assessed.
811 GPs (77%) returned the questionnaire. 48% of GPs did not feel confident with making a diagnosis of CFS/ME and 41% did not feel confident in treating it. 72% of GPs accepted CFS/ME as a recognisable clinical entity and those GPs had significantly more positive attitudes. Three other key factors that were significantly, positively associated with GPs' attitudes were knowing someone socially with CFS/ME, being male and seeing more patients with the condition in the last year.
Despite the publication of guidance for GPs on CFS/ME, confidence in making a diagnosis and management was found to be low. Educational initiatives and guidance for GPs should stress the importance of accepting CFS/ME as a recognisable clinical entity, as this is linked to having a positive attitude and could lead to improved confidence to make a diagnosis and treat CFS/ME patients.
Butchart, J. Empowerment for patients with medically unexplained symptoms. Journal of the Royal Society of Medicine, 2005, 98, 4, 187.
Letter responding to Salmon and Hall (ibid, 2004, 97, 53). “We are teaching our patients to blame themselves for their illnesses. You have had a heart attack because you chose to smoke, ate the wrong foods, took too little exercise. In the past, people viewed illness as poor luck but we are now learning a new aetiology - that of individual behavioural determinism. The message is clear. Your heart attack is your own fault.
This is a deeply unpalatable message for the unwell and generates an emotionally charged conflict, especially apparent in syndromes of medically unexplained symptoms. The clinical challenge is to lessen patients' feeling of responsibility for the cause of the illness whilst at the same time helping them to establish a feeling of control and power over the symptoms. Salmon and Hall highlight the danger of empowerment when doctors and patients focus only on symptom control and ignore issues of aetiology. Empowering explanations must address both cause and control of illness if they are to alleviate rather than exacerbate the patient's distress.”
Cleare, AJ., Messa, C., Rabiner, EA and Grasby, PM. Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635. Biological Psychiatry, 2005, 57, 3, 239-246.
Research from neuroendocrine challenge and other indirect studies has suggested increased central 5-HT function in CFS and increased 5-HT1A receptor sensitivity. The researchers assessed brain 5-HT(1A) receptor binding potential directly using the specific radioligand [11C]WAY-100635 and positron emission tomography (PET). They selected 10 patients from a tertiary referral clinic who fulfilled the Oxford and CDC 1994 criteria for CFS. To assemble a homogenous group and avoid confounding effects, only subjects who were completely medication-free and did not have current comorbid psychiatric illness were enrolled. The results were compared to those from 10 healthy control subjects.
There was a widespread reduction in 5-HT1A receptor binding potential in CFS relative to control subjects. This was particularly marked in the hippocampus bilaterally, where a 23% reduction was observed.
“There is evidence of decreased 5-HT1A receptor number or affinity in CFS. This may be a primary feature of CFS, related to the underlying pathophysiology, or a finding secondary to other processes, such as previous depression, other biological changes or the behavioral consequences of CFS.”
[Ed. Note: The GHQ score for distress was on the high side, and this may have affected the results.]
Darbishire, L., Seed, P and Ridsdale, L. Predictors of outcome following treatment for chronic fatigue. British Journal of Psychiatry, 2005, 186, 350-351
We explored the role of baseline characteristics of 105 patients who presented with at least 3 months of fatigue in primary care in determining outcome following either graded exercise or cognitive-behavioural therapy (CBT).
Only 31% met the criteria for CFS (CDC '94) and only 5% were members of a ME support group. 60% had a history of psychiatric disorder. Meeting the criteria for CFS was the most powerful predictor of poor outcome and this negative effect was enhanced by greater functional impairment or greater perceived negative consequences, but was not further enhanced by both (there was a high correlation between them e.g. CFS and final fatigue, baseline fatigue and functional impairment). Belief in a psychological cause was not significantly correlated with final fatigue (-.147), neither was perceived control.
[Ed. Note: The mean baseline HAD anxiety score was comparatively high].
Fossey, M., Libman, E., Bailes, S., Baltzan, M., Schondorf, R., Amsel, R and Fichten, CS. Sleep quality and psychological adjustment in chronic fatigue syndrome. Journal of Behavioral Medicine, 2004, 27, 6, 581-605.
Individuals with CFS complain of fatigue and poor sleep-symptoms that are often attributed to psychological disturbance. To assess the nature and prevalence of sleep disturbance in CFS and to investigate the widely presumed presence of psychological maladjustment, we examined sleep quality, sleep disorders, physical health, daytime sleepiness, fatigue, and psychological adjustment in three samples. individuals with CFS; a healthy control group; and individuals with a definite medical diagnosis: narcolepsy. Outcome measures included physiological evaluation (polysomnography), medical diagnosis, structured interview, and self-report measures.
The results indicated that the CFS sample had a very high incidence (58%) of previously undiagnosed primary sleep disorder such as sleep apnea/hypopnea syndrome and restless legs/periodic limb movement disorder. They also had very high rates of self-reported insomnia and non-restorative sleep. Narcolepsy and CFS participants were very similar on psychological adjustment: both these groups had more psychological maladjustment than did control group participants.
Our data suggest that primary sleep disorders in individuals with CFS are underdiagnosed in primary care settings and that the psychological disturbances seen in CFS may well be the result of living with a chronic illness that is poorly recognized or understood.
Moss, J. Development of a functional ability scale for children and young people with myalgic encephalopathy (ME)/chronic fatigue syndrome CFS). Journal of Child Health Care, 2005, 9, 20-30.
The numerous symptoms and unpredictable pattern of myalgic encephalopathy (ME) make it difficult to describe, especially for children. It was left to carers to guess what the child could achieve each day, often leading to over/underestimates. A functional ability scale was needed, that children and young people themselves designed. A new scale was developed from the Moss Ability Scale using the critique of 251 children and young people from the Association of Young People with ME (AYME). Responding to the shift in emphasis towards patients taking an active role in their own care, it was felt these young people would know whether the scale measured what it had set out to measure, and were asked questions on the face and content validity of the scale. There was a 99 percent agreement between the young people that the final scale was ‘workable’ or better.
Ong, BN., Evans, D and Bartlam, A. A patient’s journey with myalgic encephalomyelitis. BMJ 2005, 330, 648-650.
Case history of patient with a wide range of symptoms which followed a concussion. This account relates her feelings and those of her doctor, who was willing to be informed about ME by her.
Rakib, A., White, PD., Pinching, AJ., Hedge, B., Newbery, N., Fakhoury WK and Priebe S. Subjective quality of life in patients with chronic fatigue syndrome. Quality of Life Research 2005, 14, 1, 11-19.
The aim of this study was to (1) assess Subjective Quality of Life (SQOL) of patients with CFS using a generic concept and to compare the findings with those in groups with mental disorders and healthy subjects, and (2) investigate whether and, if so, to what extent sociodemographic and clinical variables predict SQOL in CFS patients.
Seventy-three patients diagnosed with CFS (Oxford criteria) were randomly selected and interviewed from two specialised clinics. SQOL was assessed on the Manchester Short Assessment of Quality of Life (MANSA) and Health-Related Quality of Life (HRQOL) on the Medical Outcome Study Short-Form 36 (MOS) SF-36. A battery of mood and symptom questionnaires, including the Symptom Checklist Questionnaire (SCL-90-R), was administered to assess various aspects of symptomatology as potential predictor variables. Multiple regression analyses were conducted to identify predictors of SQOL.
Overall, SQOL was low in CFS patients and less favourable than in groups with mental disorders and healthy subjects. Satisfaction was particularly low with life as a whole, leisure activities and financial situation. Whilst SQOL was only moderately correlated with HRQOL, the SCL-90-R score, especially SCL-90-R Depression scale score, was the best predictor of SQOL explaining 35% of the variance. HRQOL and generic SQOL appear distinct despite some overlap. The findings underline that SQOL is significantly disrupted in CFS patients. Depressive symptoms are statistically the strongest 'predictor' of SQOL, although the direction of the relationship is not established.
These data suggest that treatment of depression associated with CFS, regardless of causation, could help to improve SQOL in CFS patients.
Shin YI, Lee MS. Qi therapy (external qigong) for chronic fatigue syndrome: case studies. American Journal of Chinese Medicine, 2005, 33, 1, 139-141.
The aim of this study was to examine the effects of Qi therapy (QT) on the symptoms of CFS, including fatigue and complications.
QT affected the experience of mental and emotional relaxation in the subjects of these case studies, who also gained strength to overcome their pain and fatigue. Although the results of these two case studies may not constitute conclusive evidence, they provide a foundation for the exploration of QT as a complementary therapy in the reduction of negative symptoms of CFS.
Stouten, B. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Services Research, 2005, 5:37 (As per 13th May 2005).
A recent article by Reeves et al. on the identification and resolution of ambiguities in the 1994 CFS research case definition recommended the Checklist Individual Strength, the Chalder Fatigue Scale, and the Krupp Fatigue Severity Scale for evaluating fatigue in CFS studies. To be able to discriminate between various levels of severe fatigue, extreme scoring on the individual items of these questionnaires must not occur too often.
We derived an expression that allows us to compute a lower bound for the number of items with the maximum item score for a given study from the reported mean scale score, the number of reported subjects, and the properties of the fatigue rating scale. Several CFS studies that used the recommended fatigue rating scales were selected from literature and analyzed to verify whether abundant extreme scoring had occurred.
Extreme scoring occurred on a large number of the items for all three recommended fatigue rating scales across several studies. The percentage of items with the maximum score exceeded 40% in several cases. The amount of extreme scoring for a certain scale varied from one study to another, which suggests heterogeneity in the selected subjects across studies. Because all three instruments easily reach the extreme ends of their scales on a large number of the individual items, they do not accurately represent the severe fatigue that is characteristic for CFS. This should lead to serious questions about the validity and suitability of the Checklist Individual Strength, the Chalder Fatigue Scale, and the Krupp Fatigue Severity Scale for evaluating fatigue in CFS research.
See: http://www.biomedcentral.com/1472-6963/5/37
Stulemeijer, M., de Jong, LWAM., Fiselier, TJW., Hoogveld, SWB and Bleijenberg, G. Cognitive behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial. BMJ, 2005, 330, 14-17. Also bmj.com (corrected version) December 14th, 2004.
[Ed. Note: Stulemeijer et al responded to a point made by Stouten about school attendance (7th March). In addition, two of the four errors noted earlier by Stouten, Goudsmit and Howes (11.2.2005) were formally corrected on the 9th April 2005 (330, 7481, 14, 820). “In the paper by Maja Stulemeijer and colleagues the drop-out rate from treatment in the group allocated to immediate cognitive behaviour therapy was given as 19% (BMJ 2005; 330:14-7, 1 Jan). This should have been 17% (6/35). Also, in the footnote to table 4 (full version only) the cut-off score on the fatigue was given as >= 35.7. As the paper indicates that patients were considered to be improved if the score was <35.7, reflecting less fatigue, the cut off in the footnote would be better presented as <35.7 to match the presentation in the text.”
A letter by Chaudhuri commenting on other flaws was published 2nd April (2005, 330, 789). With reply by Stulemeijer et al (ibid p. 790).
A rapid response to the latter by Du Pre (8th April) noted some of the evidence of ongoing pathology which undermines the CBT school’s view that people with CFS wrongly believe that their symptoms are made worse by exercise. “This statement exhibits a misunderstanding of the disease Myalgic Encephalomyelitis/CFS as a recoverable, psychological condition… And the disorder is clearly not fatigue, but is more accurately represented as muscle myopathy, reduced oxidative muscle metabolism, and cardiac insufficiency…
Bleijenberg and his colleagues are bypassing solid, substantive studies which counter their statements about Myalgic Encephalomyelitis/CFS. The end result of this is undue suffering in the patient community and an unjust portrayal which undermines the reality of the seriousness of this neuroimmune disease which… is worsened by aerobic exercise as shown clearly in the brain SPECT scan evidence in Dr. Byron Hyde's book, The Clinical and Scientific Basis for Myalgic Encephalomyelitis/CFS.
As a former college professor and long-distance runner, to be unfairly categorized in this way is a disturbing trend considering the large body of research which militates against the position set forth by Bleijenberg.”
Additional issues reported to the editors of the BMJ include the following:
1. In Table 3, the reported 95% confidence interval (-0.3, -0.7) for the symptom “sore throat” is inconsistent with the reported treatment effect (the second number might be 0.7 instead of -0.7).
2. The reported mean difference between groups for the outcome “physical functioning” in Table 5 may be wrong (10 should be -10), and the corresponding 95% confidence interval (-3.3 to 21.1) is incorrect (it seems that someone has accidentally copied the 95% confidence interval from the outcome “fatigue severity”).
3. The reported number of subjects and the reported mean scores at zero months as well as at five months for the outcome “school attendance” in Table 5 are inconsistent with the numbers in Table 2 (e.g. according to Table 5 the mean school attendance score at zero months of the passive and the active group equals (10x21.0+23x59.7)/33 = 47.97, but according to Table 2 it should be 46.2; it is possible that the authors forgot to mention that some participants were excluded from the active and passive groups in Table 5 as they were probably no longer required to attend school).
4. The Gpower computer program that was used to perform the power calculation requires the so-called effect size, which is missing from the article. This makes it impossible to interpret the sample size calculation.
5. The first two p-values in Table 4 do not match the number of subjects in that table (21/35, 7/34 and 22/35, 8/34 both correspond to p=0.001 instead of p=0.01).
Van de Putte, EM., Uiterwaal, CSPM., Bots, ML., Kuis,W., Kimpen, JLL and Engelbert , RHH. Is chronic fatigue syndrome a connective tissue disorder? A cross-sectional study in adolescents. Pediatrics. 2005, 115, 4, e415-422.
To investigate whether constitutional laxity of the connective tissues is more frequently present in adolescents with CFS than in healthy controls. Increased joint hypermobility in patients with CFS has been previously described, as has lower blood pressure in fatigued individuals, which raises the question of whether constitutional laxity is a possible biological predisposing factor for CFS.
This was a cross-sectional study. Samples: Thirty-two adolescents with CFS (CDC criteria ’94) referred to a tertiary hospital and 167 healthy controls.
The 32 adolescents with CFS were examined extensively regarding collagen-related parameters: joint mobility, blood pressure, arterial stiffness and arterial wall thickness, skin extensibility, and degradation products of collagen metabolism. Possible confounding factors (age, gender, height, weight, physical activity, muscle strength, diet, alcohol consumption, and cigarette smoking) were also measured. The results were compared with findings in 167 healthy adolescents who underwent the same examinations.
Joint mobility, Beighton score, and collagen biochemistry, all indicators of connective tissue abnormality, were equal for both groups. Systolic blood pressure, however, was remarkably lower in patients with CFS (117.3 vs. 129.7 mm Hg). Skin extensibility was higher in adolescents with CFS (mean z score: 0.5 vs. 0.1 SD). Arterial stiffness, expressed as common carotid distension, was lower in adolescents with CFS, indicating stiffer arteries (670 vs 820 mum; adjusted difference: -110 mum). All analyses were adjusted for age, gender, body mass index, and physical activity. Additionally, arterial stiffness was adjusted for lumen diameter and pulse pressure.
These findings do not consistently point in the same direction of an abnormality in connective tissue. Patients with CFS did have lower blood pressure and more extensible skin but lacked the most important parameter indicating constitutional laxity, i.e., joint hypermobility. Moreover, the collagen metabolism measured by crosslinks and hydroxyproline in urine, mainly reflecting bone resorption, was not different. The unexpected finding of stiffer arteries in patients with CFS warrants additional investigation.
Marmion, BP et al. Long-term persistence of Coxiella burnetii after acute primary Q fever. QJM 2005 98: 237. Details of the error can be found in the journal.
Sources used include Co-Cure and Medline. Editors: EM Goudsmit PhD, S. Howes and B. Stouten PhD. With thanks to Dr. Charles Shepherd and Ray Colliton.
This update is for personal use only. Not all abstracts were checked with the original document and there may be errors due to conversion between word processors. For reliable information, please refer to the original articles.
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