ME and CFS References

NEUROLOGY

Caseras, X., Mataix-Cols, D., Giampietro, V., Rimes, KA., Brammer, M., Zelaya, F., Chalder, T and Godfrey, EL. Probing the working memory system in chronic fatigue syndrome: a functional magnetic resonance imaging study using the n-back task. Psychosomatic Medicine, 2006, 68 [Epub ahead of print] DOI: 10.1097/01.psy.0000242770.50979.5f.

Up to 90% of patients with CFS report substantial cognitive difficulties. However, objective evidence supporting these claims is inconsistent. The present functional magnetic resonance imaging study examined the neural correlates of working memory in patients with CFS compared with controls.

Seventeen patients with CFS (CDC criteria ’94, five taking anti-depressants, five with panic disorder) and 12 healthy control subjects were scanned while performing a parametric version of the n-back task (0-, 1-, 2-, and 3-back).

Both groups performed comparably well and activated the verbal working memory network during all task levels. However, during the 1-back condition, patients with CFS showed greater activation than control subjects in medial prefrontal regions, including the anterior cingulate gyrus. Conversely, on the more challenging conditions, patients with CFS demonstrated reduced activation in dorsolateral prefrontal and parietal cortices. Furthermore, on the 2- and 3-back conditions, patients but not control subjects significantly activated a large cluster in the right inferior/medial temporal cortex. Trend analyses of task load demonstrated statistically significant differences in brain activation between the two groups as the demands of the task increased.

These results suggest that patients with CFS show both quantitative and qualitative differences in activation of the working memory network compared with healthy control subjects. It remains to be determined whether these findings stay stable after successful treatment.

PHYSIOLOGY AND BIOCHEMISTRY

Cook, DB., Nagelkirk, PR., Poluri, A., Mores, J and Natelson, BH. The influence of aerobic fitness and fibromyalgia on cardiorespiratory and perceptual responses to exercise in patients with chronic fatigue syndrome. Arthritis and Rheumatism, 2006, 54, 10, 3351-3362.

The aim of this study was to investigate cardiorespiratory and perceptual responses to exercise in patients with CFS, accounting for comorbid fibromyalgia (FM) and controlling for aerobic fitness.

Twenty-nine patients with CFS (CDC criteria ’94), 23 patients with CFS plus FM, and 32 controls completed an incremental bicycle test to exhaustion. Cardiorespiratory and perceptual responses were measured. Results were determined for the entire sample and for 18 subjects from each group matched for peak oxygen consumption.

In the overall sample, there were no significant differences in cardiorespiratory parameters between the CFS group and the controls. However, the CFS plus FM group exhibited lower ventilation, lower end-tidal CO2, and higher ventilatory equivalent of carbon dioxide compared with controls, and slower increases in heart rate compared with both patients with CFS only and controls. Peak oxygen consumption, ventilation, and workload were lower in the CFS plus FM group. Subjects in both the CFS group and the CFS plus FM group rated exercise as more effortful than did controls. Patients with CFS plus FM rated exercise as significantly more painful than did patients with CFS or controls. In the subgroups matched for aerobic fitness, there were no significant differences among the groups for any measured cardiorespiratory response, but perceptual differences in the CFS plus FM group remained.

With matching for aerobic fitness, cardiorespiratory responses to exercise in patients with CFS and CFS plus FM are not different from those in sedentary healthy subjects. While CFS patients with comorbid FM perceive exercise as more effortful and painful than do controls, those with CFS alone do not. These results suggest that aerobic fitness and a concurrent diagnosis of FM are likely explanations for currently conflicting data and challenge ideas implicating metabolic disease in the pathogenesis of CFS.

[Ed. Note: The presence of post-exertional fatigue was not required for inclusion in this study, which may explain a number of the findings.]

Hannestad, U., Theodorsson, E., and Evengård, B. β-Alanine and γ-aminobutyric acid in chronic fatigue syndrome. Clinica Chimica Acta, 2006 July 14; [Epub ahead of print]. doi:.1016/j. cca.2006.07.004.

Due to the occurrence of sleep disturbances and fatigue in CFS, an investigation was performed to examine if there is an abnormal excretion of γ-aminobutyric acid (GABA) and/or its structural analogue β-alanine in the urine from CFS patients (CDC criteria ’94). Both GABA and β-alanine are inhibitory neurotransmitters in the mammalian central nervous system.

The 24 h urine excretion of GABA and β-alanine was determined by isotope dilution gas chromatography mass spectrometry in 33 CFS patients and 43 healthy controls. The degree of symptoms in both patients and controls was measured by grading of three typical CFS symptoms using a Visual Analogue Scale.

Men had a significantly higher excretion of both β-alanine and GABA than women. Comparing CFS patients with healthy controls showed no significant difference in excretion of neither β-alanine nor GABA. No correlation was found between the excretion of β-alanine or GABA and any of the three characteristic CFS symptoms measured. However, two female and two male CFS patients excreted considerably higher amounts of β-alanine in their 24 h urine samples than control subjects. “We were unable to detect the two substances CFSUM1 and CFSUM2”.

Increased excretion of β-alanine was found in a subgroup of CFS patients, indicating that there may be a link between CFS and β-alanine in some CFS patients.

PSYCHOLOGY AND PSYCHIATRY

Thomas, MA and Smith, AP. An investigation of the long-term benefits of antidepressant medication in the recovery of patients with chronic fatigue syndrome. Human Psychopharmacology: Clinical and Experimental, 2006 September 18; [Epub ahead of print] DOI: 10.1002/hup.805.

Two hundred and seventy-five patients with CFS (CDC criteria ’94) completed measures assessing illness history, global ratings of well being, sleep, activity and psychopathology at baseline, 6 months, 18 months and 3 year follow-up.

Forty-nine of these patients had been prescribed antidepressant medication, namely tricyclic drugs or selective serotonin re-uptake inhibitors (SSRI). Data from the current study suggests that patients in the antidepressant medication group recovered at a faster rate over time when compared to the untreated patient sample. In addition, the positive effects of antidepressant therapy were maintained at the 3-year follow-up point.

It appears from these data that the SSRI in particular are responsible for improvements in the condition. Most importantly, these improvements include a reduction in the levels of fatigue recorded by patients. These findings have not been demonstrated in previous studies of the effect of antidepressant therapy for patients with this illness and this may reflect the short time periods studied in the earlier research.

Van Damme, S., Crombez, G., Van Houdenhove, B., Mariman, A and Michielsen, W. Well-being in patients with chronic fatigue syndrome. The role of acceptance. Journal of Psychosomatic Research, 2006, 61, 5, 595-599.

Research in chronic pain patients has shown that accepting the chronic nature of their illness is positively related to quality of life. The aim of this study was to investigate whether acceptance is also associated with better well-being in patients suffering from CFS.

Ninety-seven patients with CFS (CDC criteria ’94) completed a battery of questionnaires measuring fatigue, functional impairment, psychological distress, and acceptance.

Results indicated that acceptance has a positive effect upon fatigue and psychological aspects of well-being. More specifically, acceptance was related to more emotional stability and less psychological distress, beyond the effects of demographic variables, and fatigue severity. We suggest that promoting acceptance in patients with CFS may often be more beneficial than trying to control largely uncontrollable symptoms.

“...we believe that, given its strong positive effect upon physical and psychological well-being, a more explicit and systematic use of the acceptance theme might be beneficial for the majority of CFS patients. More particularly, acceptance may be an essential precondition for the therapeutic process, in which patients have to evaluate — and if necessary adjust — their former lifestyle. For many of them, this implies strategies such as activity pacing, aimed at adapting their activity level to the lowered physical limits imposed by their illness. This is particularly relevant giving the premorbid “overactive” lifestyle characterizing a substantial part of the CFS patients”.

Hawk, C., Jason, LA and Torres-Harding, S. Differential diagnosis of chronic fatigue syndrome and major depressive disorder. International Journal of Behavioral Medicine, 2006, 13, 3, 244-251.

EPIDEMIOLOGY

Hickie, I., Davenport, T., Wakefield, D., Vollmer-Conna, U., Cameron, B., Vernon, SD., Reeves, WC and Lloyd, A for the Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. British Medical Journal, 2006, 333: 575, doi:10.1136/bmj.38933.585764.AE.

The objective of this study was to delineate the risk factors, symptom patterns, and longitudinal course of prolonged illnesses after a variety of acute infections.

This was a prospective cohort study following patients from the time of acute infection with Epstein-Barr virus (glandular fever), Coxiella burnetii (Q fever), or Ross River virus (epidemic polyarthritis). The setting was the region surrounding the township of Dubbo in rural Australia, encompassing a 200 km geographical radius and 104 400 residents.

In this study, 253 patients were enrolled and followed at regular intervals (entry, 3 weeks, 6 weeks, 3 months, 12 months) by self report, structured interview, and clinical assessment. Other measures included medical, psychiatric, and laboratory evaluations at six months to apply diagnostic criteria for CFS (CDC criteria ’94) and pre-morbid and intercurrent illness characteristics were recorded to define risk factors for CFS. Self reported illness phenotypes compared between infective groups.

Prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for CFS. This post-infective fatigue syndrome phenotype was stereotyped and occurred at a similar incidence after each infection. The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological, or microbiological factors. Psychological factors which were not predictive included neuroticism.

A relatively uniform post-infective fatigue syndrome persists in a significant minority of patients for six months or more after clinical infection with several different viral and non-viral microorganisms. Post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to CFS.

[Ed. Note: The methods section suggests that all were enrolled following information from doctors and laboratories showing proven infection. It is not clear how some were included by ‘self-report’.]

THERAPEUTICS

Quarmby, L., Rimes, KA., Deale, A., Wessely, S and Chalder, T. Cognitive-behaviour therapy for chronic fatigue syndrome: Comparison of outcomes within and outside the confines of a randomised controlled trial. Behaviour Research and Therapy, 2006, October 27; [Epub ahead of print], doi:10.1016/j.brat.2006.08.019.

Outcomes for cognitive-behaviour therapy (CBT) in randomised controlled trials (RCTs) have rarely been compared to those in routine clinical practice. Taking the case of CBT for CFS, we evaluated the results of a successful RCT against those of the same treatment given in the same setting as part of routine practice.

Fatigue and social adjustment scores were compared for patients who received CBT for CFS as part of a RCT (N=30) and patients who received CBT as part of everyday clinical practice (N=384). The results in the RCT were superior to those in routine clinical practice. Between pre-treatment and 6-month follow-up, the RCT showed a larger reduction in fatigue and greater improvement in social adjustment than those in routine treatment. The changes in fatigue scores were similar for both groups during treatment but were greater in the RCT between post-treatment and follow-up.

Potential reasons for the superior results of the RCT include patient selection, therapist factors and the use of a manualised treatment protocol. Practitioners need to pay particular attention to relapse prevention and ensuring adequate follow-up in addition to encouraging patients to continue with cognitive-behavioural strategies once treatment has ended.

[Ed. Note: The fatigue scores were calculated using the bimodal scoring method, which has a low ceiling. Those with the maximum score at baseline would not have been able to record a worsening of symptoms as a result of treatment. The study excluded patients whom it was felt might not be able to complete the treatment. This may have contributed to the positive outcomes. There were no measures for cognitive functioning and somatic symptoms.]

Yuemei, L., Hongping, L., Shulan, F and Dongfang, G. The therapeutic effects of electrical acupuncture and auricular-plaster in 32 cases of chronic fatigue syndrome. Journal of Traditional Chinese Medicine, 2006, 26, 3, 163-164.

The objective was to observe the therapeutic effects of electrical acupuncture and auricular-plaster therapy for CFS. Sixty-four patients were randomly divided into two groups: 32 cases in the treatment group were treated by the electrical acupuncture and auricular-plaster therapy, and 32 cases in the control group with oral hydrocortisone.

The total effective rates were respectively 93.75% in the treatment group and 75% in the control group, with a statistically significant difference between the two groups (p< 0.05).

Electrical acupuncture and auricular-plaster therapy may show a better anti-fatigue effect than that of routine Western drugs.

REVIEWS

Chambers, D., Bagnall, A., Hempel, S and Forbes, C. Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review. Journal of the Royal Society of Medicine, 2006, 99, 506-520.

Review which promotes CBT and GET.

[Ed. Note: This review contains a number of factual errors and unfair assessments, based on the inaccurate summarising of the studies involved. For example, in relation to reference 102, the validity score should be 3, not 2. Moreover, as the results meet the criteria for ‘overall effect’ (“a statistically significant treatment effect on two or more clinical outcomes”, the study should have been assessed as showing a positive effect. Chambers et al judged it to have “no effect”. (Group differences were found for fatigue, somatic symptoms, anxiety and depression). This ‘marking down’ concerns a programme which offered medical care, pacing, emotional support and other alternatives to CBT/GET. The reference for that study is incomplete. Another study which included pacing (reference 31) was listed in the review under GET. This is despite the fact that the inclusion of pacing was noted in the first sentence of the paper in question. A study with at least four documented factual and statistical errors was given a validity score of 16 (reference 29). There is no acknowledgement of the fact that trials of GET have not shown a beneficial effect in patients with symptoms other than fatigue and emotional distress, nor did the reviewers note that CBT and GET have not resulted in significant increases in activity levels, when assessed using objective measures. Alternative explanations for the improvements, e.g. increases in self-efficacy and better pacing of activities, were not considered. The review did not include a RCT showing that counselling was as good as CBT (Ridsdale et al 2001).]

Devanur, LD and Kerr, JR. Chronic fatigue syndrome. Journal of Clinical Virology, 2006, doi:.1016/j.jcv.2006.08.013.

Review focusing on the virological and immunological aspects of CFS.

Van Staden WC. Conceptual issues in undifferentiated somatoform disorder and chronic fatigue syndrome. Current Opinion in Psychiatry, 2006, 19, 613-618.

The differences and/or similarities between undifferentiated somatoform disorder and CFS have not been studied, conceptually or empirically. The literature fails to present discriminant validity of CFS in relation to undifferentiated somatoform disorder. Some patients experience their fatigue as being exclusively physical and not as mental, which is prima facie peculiar, for fatigue is necessarily a mental experience. One is not able to experience fatigue without a mind (or a brain). This experience is characterized as a 'mindless' fatigue, underpinned by pathological reductionist thinking. By not recognizing this critical feature, diagnostic endeavours may perpetuate the problem as a function of the patient's difficulty.

Proponents of CFS should distinguish CFS from undifferentiated somatoform disorder, if CFS is a distinct entity at all. Further, the 'mindless' quality is a critical feature that needs consideration in refining the concept of undifferentiated somatoform disorder.

MISCELLANEOUS

Amir, M. Temporomandibular joint dysfunction as a differential diagnosis in ME/CFS patients. British Medical Journal, 2006, Rapid Responses, 5th September.

See: http://bmj.bmjjournals.com/cgi/eletters/330/7498/1012#141030

Heim, C., Wagner, D., Maloney, E., Papanicolaou, DA., Solomon, L., Jones, JF., Unger, ER and Reeves, WC. Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study. Archives of General Psychiatry, 2006, 63, 1258-1266.

A growing literature suggests that early adverse experience increases the risk for a range of negative health outcomes, including fatiguing illnesses. Identification of developmental risk factors for CFS is critical to inform pathophysiological research and devise targets for primary prevention. The aim of this study was to examine the relationship between early adverse experience and risk for CFS in a population-based sample of clinically confirmed CFS cases and non-fatigued control subjects.

This case-control study comprised 43 cases with current CFS (CDC criteria ’94, including anxiety disorders, depression and post-traumatic stress disorder) and 60 non-fatigued controls identified from a general population sample of 56146 adult residents from Wichita, Kansas. Measures included self-reported childhood trauma (sexual, physical, and emotional abuse and emotional and physical neglect) and psychopathology (depression, anxiety, and post-traumatic stress disorder) by CFS status.

The CFS cases reported significantly higher levels of childhood trauma and psychopathology compared with the controls. Exposure to childhood trauma was associated with a 3- to 8-fold increased risk for CFS across different trauma types. There was a graded relationship between the degree of trauma exposure and CFS risk. Childhood trauma was associated with greater CFS symptom severity and with symptoms of depression, anxiety, and post-traumatic stress disorder. The risk for CFS conveyed by childhood trauma increased with the presence of concurrent psychopathology.

This study provides evidence of increased levels of multiple types of childhood trauma in a population-based sample of clinically confirmed CFS cases compared with non-fatigued controls. Our results suggest that childhood trauma is an important risk factor for CFS. This risk was in part associated with altered emotional state. Studies scrutinizing the psychological and neurobiological mechanisms that translate childhood adversity into CFS risk may provide direct targets for the early prevention of CFS.

[Ed. Note: There is little information about the patients, so it is unclear how many, if any, had a post-infectious onset, post-exertional malaise or any symptom suggestive of a ME-like fatigue syndrome.]

Maes, M., Mihaylova, I and Leunis, J-C. Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): Indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. Journal of Affective Disorders, 2006 September 26; [Epub ahead of print] doi:10.1016/j.jad.2006.08.021.

There is now evidence that CFS is accompanied by immune disorders and by increased oxidative stress. The present study has been designed in order to examine the serum concentrations of IgA and IgM to LPS of gram-negative enterobacteria, i.e. Hafnia alvei; Pseudomonas aeruginosa, Morganella morganii, Proteus mirabilis, Pseudomonas putida, Citrobacter koseri, and Klebsiella pneumoniae in CFS patients (CDC criteria ’94), patients with partial CFS and 11 normal controls.

We found that the prevalences and median values for serum IgA against the LPS of enterobacteria are significantly greater in patients with CFS than in normal volunteers and patients with partial CFS. Serum IgA levels were significantly correlated to the severity of illness, as measured by the FibroFatigue scale and to symptoms, such as irritable bowel, muscular tension, fatigue, concentration difficulties, and failing memory.

The results show that enterobacteria are involved in the etiology of CFS and that an increased gut-intestinal permeability has caused an immune response to the LPS of gram-negative enterobacteria. It is suggested that all patients with CFS should be checked by means of the IgA panel used in the present study and accordingly should be treated for increased gut permeability.

[Ed. Note: It is not clear how many patients were included in which group. The authors did not report details of a test for gut permeability, or the results.]

McCue, P., Buchanan, T and Martin, CR. Screening for psychological distress using internet administration of the Hospital Anxiety and Depression Scale (HADS) in individuals with chronic fatigue syndrome. British Journal of Clinical Psychology, 2006, 45, 4, 483-498.

The objective was to investigate the factor structure and internal consistency of the Hospital Anxiety and Depression Scale (HADS) in individuals with CFS using an Internet administered version of the instrument. CFS was assessed using an instrument including questions from both the CDC and London criteria (for ME). Confirmatory factor analysis (CFA) and internal consistency analysis of the HADS was used to determine the psychometric characteristics of the instrument in individuals with CFS and a control group with data captured via an Internet data collection protocol.

CFA revealed that a 3-factor solution offered the most parsimonious account of the data. Internal consistency estimations of the anxiety and depression subscales were found to be acceptable for both groups. The CFS group was found to have significantly higher HADS-assessed anxiety and depression scores compared with controls, however, there was also evidence found that Internet administration of the instrument may inflate HADS subscale scores as an artifact of testing medium.

The HADS is suitable for use for screening individuals with CFS in terms of the factor structure of the instrument, however, clinicians should be aware that this instrument assesses 3 domains of affective disturbance rather than 2 as is interpreted within the current HADS anxiety and depression subscale scoring system. Researchers need also be aware that Internet administration of negative affective state measures such as the HADS is likely to inflate scores and need to ensure that comparisons between clinical groups are made with control group data gathered using the same collection methodology.

O'Dowd, H., Gladwell, P., Rogers, CA., Hollinghurst, S and Gregory, A. Cognitive behavioural therapy in chronic fatigue syndrome: a randomised controlled trial of an outpatient group programme. Health Technology Assessment, 2006, 10, 37, 1-140.

The objective was to test the hypothesis that group CBT will produce an effective and cost-effective management strategy for patients in primary care with chronic fatigue syndrome/myalgic encephalopathy (CFS/ME).

A double-blind, randomised controlled trial was adopted with three arms. Outcomes were assessed at baseline and 6 and 12 months after first assessment and results were analysed on an intention-to-treat basis. The study was conducted in a health psychology department for the management of chronic illness in a general hospital in Bristol, UK. The sample comprised adults with a diagnosis of CFS/ME referred by their GP. The three interventions were group CBT incorporating graded activity scheduling, education and support group (EAS) and standard medical care (SMC).

The primary outcome measure was the MOS-Short Form with 36 Items (SF-36) physical and mental health summary scales. Other outcome measures included the Chalder fatigue scale, HADS, General Health Questionnaire, physical function (shuttles walked, walking speed and perceived fatigue), health utilities index and cognitive function (mood, recall and reaction times).

A total of 153 patients were recruited to the trial and 52 were randomised to receive CBT, 50 to EAS and 51 to SMC. Twelve patients failed to attend for the 12-month follow-up and 19 patients attended one follow-up, but not both. The sample was found to be representative of the patient group and the characteristics of the three groups were similar at baseline. Three outcome measures, SF-36 mental health score, Chalder fatigue scale and walking speed, showed statistically significant differences between the groups. Patients in the CBT group had significantly higher mental health scores (p=0.019), less fatigue (p=0.027) and were able to walk faster (p=0.0013) than patients in the SMC group. CBT patients also walked faster and were less fatigued than those randomised to EAS (walking speed: p=0.047; fatigue: p=0.011). Overall, no other statistically significant difference across the groups was found, although for many measures a trend towards an improved outcome with CBT was seen. Except for walking speed, which, on average, increased by +0.87 shuttles (p=0.029) between the 6- and 12-month follow-ups, the scores were similar at 6 and 12 months.

At baseline, 30% of patients had an SF-36 physical score within the normal range and 52% had an SF-36 mental health score in the normal range. At 12 months, the physical score was in the normal range for 46% of the CBT group, 26% of the EAS group and 44% of SMC patients. For mental health scores, the percentages were CBT 74%, EAS 67% and SMC 70%. Of the CBT group, 32% showed at least a 15% increase in physical function and 64% achieved a similar improvement in their mental health. For the EAS and SMC groups, this improvement in physical and mental health was achieved for 40 and 60% (EAS) and 49 and 53% (SMC), respectively. The cost-effectiveness of the intervention proved very difficult to assess and did not yield reliable conclusions.

Group CBT did not achieve the expected change in the primary outcome measure as a significant number did not achieve scores within the normal range post-intervention. The treatment did not return a significant number of subjects to within the normal range on this domain; however, significant improvements were evident in some areas. Group CBT was effective in treating symptoms of fatigue, mood and physical fitness in CFS/ME. It was found to be as effective as trials using individual therapy in these domains. However, it did not bring about improvement in cognitive function or quality of life. There was also evidence of improvement in the EAS group, which indicates that there is limited value in the non-specific effects of therapy. Further research is needed to develop better outcome measures, assessments of the broader costs of the illness and a clearer picture of the characteristics best fitted to this type of intervention.

[Ed. Note: The patients were not diagnosed using research criteria. Those with normal MOS-SF PF scores at baseline would not have met the current CDC criteria for CFS. Studies elsewhere have shown that active patients do less well on CBT programmes including the GET component. See below).

Sankey, A., Hill, CM., Brown, J., Quinn, L and Fletcher, A. A follow-up study of chronic fatigue syndrome in children and adolescents: symptom persistence and school absenteeism. Clinical Child Psychology and Psychiatry, 2006, 11, 1, 126-138.

This is a follow-up study of 28 young people aged between 7 and 17 meeting the Oxford criteria for the diagnosis of CFS treated in a specialist paediatric/psychiatric service. Retrospective case note analysis revealed a wide range and duration of symptoms together with high levels of school absenteeism prior to the diagnosis. The mean follow-up interval after discharge from the specialist service was 3 years and although most of the young people regarded themselves as fully recovered by this time, improvement was variable and about one third were still experiencing disabling symptoms. The illness had impacted on the education or career plans of all the young people to some extent with 15 experiencing difficulty returning to school.

This article highlights the need for early recognition and diagnosis of CFS in young people and the importance of continuing paediatric support to reduce symptom persistence in the sensitive recovery period. Maintaining school attendance by close liaison between health and education services both before and after diagnosis and treatment is also vital if long-term morbidity is to be reduced.

Torenbeek, M., Mes, CAJ., van Liere, MJ., Schreurs, KMG., ter Meer, R., Kortleven, GC and Warmerdam, CGM. Favourable results of a rehabilitation programme with cognitive behavioural therapy and graded physical activity in patients with the chronic fatigue syndrome. Nederlands Tijdschrift voor Geneeskunde, 2006, 150, 2088-2094.

The objective was to determine whether a specific course of interdisciplinary rehabilitation might lead to clinically significant changes in fatigue, experienced disability and physical function in patients with CFS (CDC criteria ’94, operationalised).

‘Het Roessingh’, a rehabilitation centre in Enschede, the Netherlands, has developed an interdisciplinary clinical rehabilitation programme for patients with CFS in cooperation with the ‘Nijmeegs Kenniscentrum Chronische Vermoeidheid’ [Chronic-Fatigue Knowledge Centre] in Nijmegen, the Netherlands. In this programme, physical, mental and social activities are gradually increased on the basis of cognitive behavioural principles and graded activity. Of the 127 successive persons who enrolled for the therapy during the period from August 2000 to December 2004, 99 fulfilled the inclusion criteria; they had a median duration of symptoms of 6 years. The results of treatment were evaluated by a measurement with the ‘Checklist individuele spankracht’ [Checklist individual muscle tone] before and after treatment and the scores on the ‘Patiëntspecifieke beperkingen’ [Patient-specific disability] and the Short form-36. The measured data were complete in 74 patients.

Before rehabilitation, the levels of fatigue, disability and distress were high. After treatment, the studied population showed significant improvement in fatigue, experienced disability and physical function. The magnitude of the improvement was generally ‘average’. At the end of treatment, 70% of the patients were clinically less fatigued, 68% experienced less disability and 55% functioned better physically. In 34% the level of fatigue was normalised after treatment, but 9.5% of the patients had more fatigue.

The rehabilitation programme offered for CFS led to significant improvements in function and fatigue.

[Ed. Note: This study had no control group or follow-up. The MOS-SF score for physical functioning following treatment revealed significant residual disability (mean 59.9). The patients who were least active showed the most improvement.]

Van Houdenhove, B. What is the aim of cognitive behaviour therapy in patients with chronic fatigue syndrome? Psychotherapy and Psychosomatics, 2006, 75, 6, 396-397.

Letter responding to article by Bazelmans et al (ibid, Psychother Psychosom 2005; 74: 218) which reported negative results with group CBT.

Although the participants reported less fatigue, there was no improvement in physical functioning. According to Van Houdenhove, “the patients’ symptomatic amelioration might have been due to the fact that they had learned to better manage their energy, not exceed their limits and avoid peaks of activity which might eventually have resulted in a decrease of their global activity level.”

Regarding the aims of CBT, van Houdenhove writes that some authors suggest that the therapist should mainly incite patients to diminish their somatic focus and correct inappropriate physical attributions. However, the usefulness of this goal is doubtful since the majority of patients with CFS and the largely overlapping FM syndrome seems to accept a combined psychological/somatic causation of their illness. According to other authors, the therapist should in the first place tackle the patients’ activity avoidance or irregular activity patterns (outburst of activity followed by prolonged periods of rest), and stimulate them to engage in a graded exercise programme in order to fight physical deconditioning. However, most CFS patients do not show kinesiophobia and loss of exercise capacity does not seem to play a major role in the pathophysiology of CFS. Moreover, recent physical therapists do not recommend ‘pure’ graded exercise therapy in CFS patients (i.e. progressively increasing physical effort irrespective of possible symptom worsening), but modulate exercises by an individualized pacing scheme. Finally, some CBT therapists are convinced that patients should, at the end of the therapy, stop considering themselves as CFS sufferers, even claim their therapy being curative, while others point to the patients’ lasting vulnerability necessitating long-term adaptation to prevent relapse.

“In our own daily practice with patients suffering from CFS/FM, we base our group CBT programme on the following pathophysiological working hypothesis: both CFS and FM result from a ‘loss of resilience’ of the stress system, after a prolonged period of physical or mental overburdening in which the system functions ‘in overdrive’. Given the fact that direct treatment of this neurobiological dysregulation is at present not available, we explain to the patients that the recovery of their stress system might be indirectly facilitated under the following conditions: First, they should accept their ailment and functional limitations and work through the painful grieving process resulting from the fact that CFS means giving up many important things in life. Second, they should realistically adapt to their effort intolerance by learning to carefully pace activities in order to avoid post-exertional malaise reflecting abnormal immune activation. In many patients, this implies abandoning their previous ‘overactive’ lifestyles, which may be rooted in narcissistic, perfectionistic or counter-dependent tendencies. Third, they should try to gradually increase their physical and mental activity level, again without provoking post-exertional malaise. And fourth, they should realize that long-term readjustment of lifestyle, life-goals and priorities is a condition sine qua non to maintain symptomatic amelioration and regain stress system resilience.

In sum, if our hypothesis is correct (namely that the aetiopathogenesis of CFS/FM is based on long-lasting physical and/or mental overburdening, leading to severe and persistent disturbances of the stress system in vulnerable individuals), the aim of CBT should be to help patients find a ‘new equilibrium’, taking fully account of their personal illness and life history.”

Vermeulen, R. Translation and validation of the Dutch language version of the CDC Symptom Inventory for assessment of chronic fatigue syndrome (CFS). Population Health Metrics, 2006, 4, 12. doi:10.1186/1478-7954-4-12.

In a study by Wagner et al. the CDC Symptom Inventory was validated in a population that was selected from the inhabitants of a city in the USA, and proved reliable for the assessment of the symptoms accompanying the CFS. The Dutch translation of the CDC Symptom Inventory is compared to the original, and the psychometric properties are presented for patients in a tertiary care setting.

A total of 139 consecutive patients who visited the CFS Centre Amsterdam for the first time were asked to complete the CDC Symptom Inventory in the Dutch Language Version (DLV) together with the usual set of questionnaires. Sixty-one patients had chronic fatigue (CF) and 78 patients fulfilled the CDC 1994 criteria for CFS. Forty-three healthy accompanying persons completed the CDC Symptom Inventory DLV, the Physical Functioning scale of the Medical Outcome Survey Short Form-36 DLV, and the Fatigue and Concentration scales of the Checklist Individual Strength (CIS-20).

The healthy control group contained fewer women and was overall older than the patient groups. The influence of gender on the CDC Symptom Inventory DLV was significant but the effect of age was not. The Dutch version had a good internal consistency and convergent validity. The results were comparable to the original English version, but the sex-related difference needs further study.

The Dutch version of the CDC Symptom Inventory is a reliable tool for the assessment of the secondary criteria for CFS. The results show that it is comparable to the outcome of studies in English-speaking countries.

http://www.pophealthmetrics.com/content/pdf/1478-7954-4-12.pdf

Vervoort, T., Crombez, G., Buysse, A., Goubert, L., De Backer, T and Ickes, W. Brief Report: The accuracy of parents for the thoughts and feelings of their adolescent suffering from chronic fatigue: a preliminary study of empathy. Journal of Pediatric Psychology, 2006; September 29, doi:10.1093/jpepsy/jsl032.

This study examined the actual and estimated empathic accuracy (EA) of the parents of adolescents with CFS. The actual EA of both parents (n=24) was assessed in relation to the thoughts and feelings of their child (n=14) about CFS and about other life events. Adolescents were also asked to estimate the parents' EA.

For the actual EA, both parents were significantly less accurate regarding the adolescent's thoughts and feelings about CFS than about other life events. Fathers were just as empathically accurate as mothers. For the estimated EA, however, results indicated that adolescents perceived their mother to be more empathically accurate than their father. Actual EA and estimated EA about CFS were negatively correlated for fathers, not for mothers.

Results are discussed in terms of the importance of assessing EA in relation to other dimensions of empathic understanding and distress in the observer.

[Ed. Note: the illness was diagnosed by doctors with specialist knowledge of CFS. No set criteria were used.]

Wilbur, J., Shaver, J., Kogan, J., Buntin, M and Wang, E. Menopausal transition symptoms in midlife women living with fibromyalgia and chronic fatigue. Healthcare for Women International, 2006, 27,  7, 600-614.

SPECIAL ISSUES

Carruthers, B. Definitions and aetiology of Myalgic Encephalomyelitis (ME): how the Canadian Consensus Clinical Definition of ME works. Journal of Clinical Pathology, 2006, 25 August; [Epub ahead of print]. doi:10.1136/jcp.2006.042754.

Colby, J. Special Problems of children with ME/CFS and the enteroviral link. Journal of Clinical Pathology, 2006, 1st September; [Epub ahead of print]. doi:10.1136/jcp.2006.042606.

“...the Tymes Trust has reported that many affected children struggle for recognition of their needs and feel bullied by medical and educational professionals. Children should have time to recover sufficiently before returning to school; sustainable, energy-efficient and often home-based education is important here, to fulfil legal obligations. Research is needed into viruses that trigger childhood ME, for example, enteroviruses, and into the neurocognitive defects caused by ME. We should recognise the value of previous biological research and records of outbreaks and I recommend that ME be made notifiable due to the encephalitic nature of the effects commonly reported in this illness.”

Gibson, I. A new look at chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Journal of Clinical Pathology, 2006, 25 August; [Epub ahead of print]. doi:10.1136/jcp.2006.042432.

Hooper, M. Myalgic Encephalomyelitis (ME): a review with emphasis on key findings in biomedical research. Journal of Clinical Pathology, 2006, 1st September; [Epub ahead of print,] doi:10.1136/jcp.2006.042408.

Kerr, JR., Christian, P., Hodgetts, A., Langford, PR., Devanur, LD., Petty, R., Burke, B., Sinclair, LI., Richards, SCM., Montgomery, J., McDermott, C., Harrison, TJ., Kellam, P., Nutt, DJ and Holgate, ST. Current research priorities in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): disease mechanisms, a diagnostic test and specific treatments. Journal of Clinical Pathology, 2006, 25 August; [Epub ahead of print]. doi:10.1136/jcp.2006.042374.

CFS is an illness characterised by disabling fatigue of at least 6 months duration which is accompanied by various rheumatological, infectious and neuropsychiatric symptoms. A collaborative study group has been formed in order to address the current areas for development in CFS research, namely, to develop an understanding of the molecular pathogenesis of CFS, to develop a diagnostic test, and to develop specific and curative treatments. Various groups have studied the gene expression in peripheral blood of CFS patients and of those studies which have been confirmed using polymerase chain reaction (PCR), it is clear that the most predominant functional theme is that of immunity and defence. However, we do not yet know the precise gene signature and metabolic pathways involved. Currently, this is being addressed using a microarray representing 47,000 human genes and variants, massive parallel signature sequencing (MPSS) and real-time PCR. It will be important to ensure that once a gene signature has been identified, that it is specific to CFS and does not occur in other diseases and infections. A diagnostic test is being developed using Surface-Enhanced, Laser-Desorption and Ionisation - Time of Flight (SELDI-TOF) mass spectrometry following a pilot study in which putative biomarkers were identified. And, finally, clinical trials are being planned; novel treatments which we believe are important to trial in CFS patients are interferon-α and one of the anti-tumour necrosis factor-α drugs.

Puri, BK. Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome). Journal of Clinical Pathology, 2006, 25 August; [Epub ahead of print]. doi:10.1136/jcp.2006.042424.

Evidence is put forward to suggest that myalgic encephalomyelitis, also known as CFS, may be associated with persistent viral infection. In turn, such infections are likely to impair the ability of the body to biosynthesize n-3 and n-6 long-chain polyunsaturated fatty acids by inhibiting the delta-6 desaturation of the precursor essential fatty acids alpha-linolenic acid and linoleic acid. In turn, this would impair the proper functioning of cell membranes, including cell signalling, and have an adverse effect of the biosynthesis of eicosanoids from the long-chain polyunsaturated fatty acids dihomo-γ-linolenic acid, arachidonic acid and eicosapentaenoic acid. These actions might offer an explanation for some of the symptoms and signs of myalgic encephalomyelitis. A potential therapeutic avenue may be offered by bypassing the inhibition of the enzyme delta-6-desaturase by administering both virgin cold-pressed non-raffinated evening primrose oil and eicosapentaenoic acid. The former would supply gamma-linolenic acid and lipophilic pentacyclic triterpenes. The gamma-linolenic acid can readily be converted into dihomo-γ-linolenic acid and thence arachidonic acid, while triterpenes have important free radical scavenging, cyclo-oxygenase and neutrophil elastase inhibitory activities. Furthermore, both arachidonic acid and eicosapentaenoic acid are, at relatively low concentrations, directly virucidal.

RESEARCH ON CHRONIC FATIGUE AND RELATED DISORDERS

Fowler, TA., Rice, F., Thapar, A and Farmer, A. Relationship between disabling fatigue and depression in children. Genetic study. British Journal of Psychiatry 2006, 189, 247-253.

Medically unexplained disabling fatigue in young people is familial and frequently associated with depressed mood. The aim was to examine the degree of sharing of genetic and environmental influences on the symptoms of depression and fatigue in this age group.

The parents of twins aged 8-17 years, derived from a population-based register, completed a questionnaire regarding lifetime-ever disabling fatigue in both twins. Twins aged 11 years or over completed the Mood and Feelings Questionnaire. The genetic and environmental influences on fatigue and the relationship with depression were examined using bivariate genetic analysis.

Parent-rated data were obtained for 1468 twin pairs (65%) and self-rated data from 930 older twin pairs (58%). Bivariate analysis of fatigue and depression suggested that genetic and environmental influences on disabling fatigue were mainly specific to fatigue.

Unexplained disabling fatigue in childhood is substantially familial and has mainly an independent aetiology from depression.

Kato, K., Sullivan, PF., Evengård, B and Pedersen, NL. Premorbid predictors of chronic fatigue. Archives of General Psychiatry, 2006, 63, 1267-1272.

Lipson, JG and Doiron, N. Environmental issues and work: women with multiple chemical sensitivities. Health Care for Women International, 2006, 27, 571–584.

Multiple chemical sensitivities (MCS) is an acquired condition in which exposure to low levels of chemicals causes symptoms in multiple organ systems. Some 12%–16% of the U.S. population has some level of chemical sensitivity, 80% of whom are women. Attempts to reduce chemical exposures leads to enormous life difficulties at home, school, and workplace. We base our article on an ethnographic study of MCS in the United States and Canada. We describe here themes related to work issues in terms of a general trajectory of becoming sick from work exposures, coping with toxic physical environments and dealing with coworkers and, when unable to continue working, applying for workers’ compensation, or disability status, or both.

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