ME and CFS

Medical Update

VIROLOGY/MICROBIOLOGY

Evengard, B., Briese, T., Lindh, G., Lee, S and Lipkin, WI. Absence of evidence of Borna disease virus infection in Swedish patients with chronic fatigue syndrome.  Journal of Neurovirology, 1999, 5, 5, 495-499.

Nakaya, T., Takahashi, H., Nakamur, Y., Kuratsune, H., Kitani, T., Machii, T., Yamanishi, K and Ikuta K. Borna disease virus infection in two family clusters of patients with chronic fatigue syndrome. Microbiology and Immunology, 1999, 43, 7, 679-689.

Schutzer, SE and Natelson, BH. Absence of Borrelia burgdorferi-specific immune complexes in chronic fatigue syndrome. Neurology, 1999, 53, 6, 1340-1341.

IMMUNOLOGY 

Cannon, JG., Angel, JB., Ball, RW., Abad, LW., Fagioli, L and Komaroff, AL.  Acute phase responses and cytokine secretion in chronic fatigue syndrome. Journal of Clinical Immunology, 1999, 19, 6, 414-421.

The study involved 10 CFS patients (CDC criteria '88, <3 years duration, all with post-exertional malaise) and 11 age-, sex- and activity-matched controls. Measures included levels of interleukin-6 (IL-6), assessed prior to and for 24 hours post exercise and α₂-macroglobulin (plasma protein, part of the acute phase response), assessed throughout the week.

Baseline plasma concentrations of α₂-macroglobulin were 29% higher in the CFS patients compared to the controls (p<.008) and the former also had higher levels of IL-6 (~38%). After exercise, there was a rise in IL-6 levels, but there were no significant differences between the groups. Moreover, there were no significant rises in temperature, nor in levels of plasma α₂-macroglobulin. IL-1β secretion after exercise was not related to ratings of perceived exertion in the CFS group.

"These data indicate that under basal conditions, CFS is associated with increased IL‑6 secretion which is manifested by chronically elevated plasma α₂macroglobulin concentrations". However, the modest differences suggest that "cytokine dysregulation is not a singular or dominant factor in the pathogenesis of CFS."  The researchers note that their findings are consistent with those of others and conclude that "exercise-induced exacerbation of CFS symptoms does not seem to be due to peripheral immunological mechanisms".

[Ed. note: The patients did not report fevers or an increase in fatigue after exercise, suggesting that the intensity or duration of the test was not enough to induce an immunological response.]

Moss, RB., Mercandetti, A and Vojdani, A.  TNF-α and chronic fatigue syndrome.  Journal of Clinical Immunology, 1999, 19, 314-316.

Based upon the clinical presentation of CFS, the researchers hypothesized that proinflammatory cytokines may play a role in the pathogenesis of the disease. They therefore undertook a retrospective cross-sectional study to examine the role of TNF-α in 240 patients with CFS (not defined).

The results revealed a significant increase in serum TNF-α in patients with CFS (p<0.0001) compared to non-CFS controls. "This study supports the further examination of the role of proinflammatory mediators in CFS. Furthermore, the clinical testing of TNF-α blockers and other anti-inflammatory agents for the treatment of this disease is warranted".

Smith, A., Thomas, M., Borysiewicz, L and Llewelyn, M.  Chronic fatigue syndrome and susceptibility to upper respiratory tract illness.  Journal of Health Psychology, 1999, 4, 327-335.

Over a ten-week period, 62 patients with CFS (Oxford criteria) and 44 partners or friends filled in diaries.

It was found that CFS patients reported more colds and influenza than the comparison group. They also reported greater symptom severity and use of medication for the infections; these differences were still observed when trait anxiety was covaried. The infections did not lead to long term changes in the primary symptoms of CFS.

[Ed. note: This study shows more differences between CFS as defined using broad criteria, and ME. Anecdotal reports and one study (Goudsmit 1996) have indicated that many of the latter respond to upper respiratory infections by experiencing an exacerbation of ME-type symptoms, rather those typical of colds or flu. The findings of this latest study are consistent with the literature on people suffering from 'chronic stress'. Symptoms indicative of ME, e.g. post-exertional fatigue, were not assessed.]

NEUROLOGY

Lange, G., DeLuca, J., Maldjian, JA., Lee, H-J., Tiersky, LA and Natelson, BH.  Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome.  Journal of the Neurological Sciences, 1999, 171, 1, 3-7. (Editorial, ibid, 1-2)

The researchers studied the MRI scans from three groups: 21 patients with CFS (modified CDC criteria '94) but no psychiatric disorder (CFS-No Psych), 18 people with CFS and a psychiatric disorder since illness onset (CFS-Psych), and 19 sedentary healthy controls (HC).  Two neuroradiologists who read the films were  unaware of group membership.

"The CFS-No Psych group showed a significantly larger number of brain abnormalities on T2 weighted images than the CFS-Psych and HC groups", with cerebral changes consisting mostly of "small, punctate, subcortical white matter hyperintensities, found predominantly in the frontal lobes."   No differences were found when both CFS groups were combined and compared to the HC group.

According to the researchers, this finding could explain the "more severe cognitive impairment previously reported in this subset of CFS patients". The results also support the view that CFS is not a homogeneous disorder with a single aetiology, and underline the value of the continued subclassification of patients with CFS.

PHYSIOLOGY, NEUROPHYSIOLOGY AND NEUROENDOCRINOLOGY

Gordon, R., Michalewski, HJ., Nguyen, T., Gupta, S and Starr, A. Cortical motor potential alterations in chronic fatigue syndrome. International Journal of Molecular Medicine, 1999, 4, 5, 493-499.

Hudson, M and Cleare, AJ. The 1 µg short Synacthen test in chronic fatigue syndrome.  Clinical Endocrinology, 1999, 51, 5, 625-630.

Korszun, A., Sackett-Lundeen, L., Papadopoulos, E., Brucksch, C., Masterson, L., Engelberg, NC., Haus, E., Demitrack, MA and Crofford, L. Melatonin levels in women with fibromyalgia and chronic fatigue syndrome. Journal of Rheumatology, 1999, 26, 2675-2680.

LaManca, JJ., Peckerman, A., Walker, J., Kesil, W., Cook, S., Taylor, A and Natelson, BH.  Cardiovascular response during head‑up tilt in chronic fatigue syndrome.  Clinical Physiology, 1999, 19, 2, 111-120.

Mullis, R., Campbell, IT., Wearden, AJ., Morriss, RK and Pearson, DJ. Prediction of peak oxygen uptake in chronic fatigue syndrome.  British Journal of Sports Medicine, 1999, 33, 5, 352-356.

Sacco, P., Hope, PAJ., Thickbroom, GW., Byrnes, ML and Mastaglia, FL. Corticomotor excitability and perception of effort during sustained exercise in the chronic fatigue syndrome. Clinical Neurophysiology, 1999, 110, 11, 1883-1891.

Soetekouw, PMMB., Lenders, JWM., Bleijenberg, G., Thien, T., and van der Meer, JWM. Autonomic function in patients with chronic fatigue syndrome.  Clinical Autonomic Research, 1999, 9, 334-340.

PATHOLOGY

Berg, D., Berg, LH., Couvaras, J and Harrison, H. Chronic fatigue syndrome and/or fibromyalgia as a variation of antiphospholipid antibody syndrome: an explanatory model and approach to laboratory diagnosis. Blood Coagulation & Fibrinolysis 1999, 10, 7, 435-438.

McCully, KK and Natelson, BH. Impaired oxygen delivery to muscle in chronic fatigue syndrome. Clinical Science, 1999, 97, 5, 603-608.

Twenty patients with CFS (CDC criteria '94) were compared with 12 normal sedentary subjects. Muscle oxygen delivery was measured as the rate of post-exercise and post-ischaemia oxygen-haem resaturation. Oxygen-haem resaturation was measured in the medial gastrocnemius muscle using continuous‑wavelength near-IR spectroscopy. Phosphocreatine resynthesis was measured simultaneously using ³¹P magnetic resonance spectroscopy.

The time constant of oxygen delivery was significantly reduced in CFS patients after exercise compared with that in controls. The time constant of oxygen delivery was also reduced compared with controls after cuff ischaemia. Oxidative metabolism was reduced by 20% in CFS patients, and a significant correlation was found between oxidative metabolism and recovery of oxygen delivery.

In conclusion, oxygen delivery was reduced in CFS patients compared with that in sedentary controls. This result is consistent with previous studies showing abnormal autonomic control of blood flow. Reduced oxidative delivery in CFS patients could be specifically related to CFS, or could be a non-specific effect of reduced activity levels in these patients. While these results suggest that reduced oxygen delivery could result in reduced oxidative metabolism and muscle fatigue, further studies will be needed to address this issue.

[Ed. note: If reduced activity levels were the cause of reduced oxygen delivery to muscle after exercise, one might expect to find evidence of vasoconstriction.  However, a recent study (unpublished) found vasodilation, perhaps reflecting a local response aimed at increasing oxygen levels.]

PSYCHOLOGY, NEUROPSYCHOLOGY AND PSYCHIATRY

Christodoulou, C., Deluca, J., Johnson, SK., Lange, G., Gaudino, EA and Natelson, BH.  Examination of Cloninger's basic dimensions of personality in fatiguing illness: chronic fatigue syndrome and multiple sclerosis.  Journal of Psychosomatic Research, 1999, 47, 6, 597-607.

This study compared 38 patients with CFS (modified CDC criteria '94), 40 patients with MS and 40 healthy controls.  Personality variables were measured by the Tridimensional Personality Questionnaire.

There were relatively few differences between the patient groups, suggesting that "different forms of illness can alter personality in similar ways."  Moreover, "there was no evidence that the CFS patients possessed an unusual level of negativity that would have predisposed them to develop their illness, any more so than MS patients".

Endicott, NA. Chronic fatigue syndrome in private practice psychiatry: family history of physical and mental health. Journal of Psychosomatic Research, 1999, 47, 4, 343-354.

Michiels V., de Gucht V., Cluydts R and Fischler B. Attention and information processing efficiency in patients with chronic fatigue syndrome. Belgium Journal of Clinical and Experimental Neuropsychology, 1999, 21, 5, 709-729.

Morriss, RK., Ahmed, M., Wearden, AJ., Mullis, R., Strickland, P., Appleby, L., Campbell, IT and Pearson, D. The role of depression in pain, psychophysiological syndromes and medically unexplained symptoms associated with chronic fatigue syndrome.  Journal of Affective Disorders, 1999, 55, 143-148.

Wood, B and Wessely, S. Personality and social attitudes in chronic fatigue syndrome.  Journal of Psychosomatic Research, 1999, 47, 4, 385-397.

This study on 101 patients with CFS (Oxford and CDC criteria '94) and 45 people with rheumatoid arthritis (RA) found no difference on measures of perfectionism, attitudes to mental illness, 'harm avoidance' and depression (even when fatigue-related items were removed). The RA group had higher alexithymia scores (reflecting difficulties identifying and distinguishing between feelings and bodily sensations).

The researchers conclude that the findings fail to support "media and self-help stereotypes" of the "high-achieving, over dedicated sufferer with high personal standards" and a hostility towards psychiatric explanations and interventions. They also note that depressive disorders in their CFS clinic "have been decreasing over time", which they attribute to better recognition and treatment by GPs (rather than improved diagnosis of CFS by researchers.)

[Ed. note: The archive indicates that the origin of the perfectionist stereotype was not the media, nor the self-help literature but the opinions of a small group of sceptical researchers and clinicians, one article by social anthropologists and a few anecdotal reports. The sceptical medical professionals were the main source of the insinuations that these patients shared a particularly hostile attitude towards psychiatry.]

Shlaes, JL., Jason, LA and Ferrari, JR.  The development of a chronic fatigue syndrome attitudes test. A psychometric analysis.  Evaluation & the Health Professions, 1999, 22, 4, 442-465.

Many medical professionals are sceptical of the validity of CFS, and employers often fail to appreciate the seriousness of the symptoms. Although negative attitudes greatly affect the lives of individuals with CFS, there is presently no measurement of attitudes toward this illness and people who have CFS. The purpose of the present studies was to create a scale that measures attitudes toward individuals with CFS - the Chronic Fatigue Attitudes Test (CAT) - and to assess the scale's reliability and validity.

The final 13-item scale was created using several constructs outlined in the literature regarding negative attitudes toward people with CFS, disabilities and AIDS. The original scale was found to have moderate internal reliability, construct and test-retest reliability. A study involving psychology students revealed that people who believe that CFS is not a significant medical illness also have prejudiced views about people with AIDS and a belief that people with AIDS should be treated differently by society.  The views about CFS do not appear to be related to a belief in a just world, and they're not a result of interacting with those people.

"It is possible that negative attitudes towards people with CFS are a function of past government and media portrayals of CFS as either nonexistent or a function of a neurotic, overworked, stressed way of life, as was depicted in the labelling of CFS as Yuppie Flu... The way in which the media and the government portrayed CFS may also have played a role in attributions made regarding the psychological health of people with CFS."

EPIDEMIOLOGY

Bazelmans, E., Vercoulen, JHMM., Swanink, CMA., Fennis, JFM., Galama, JMD., van Weel, C., van der Meer, JWM and Bleijenberg, G.  Chronic fatigue syndrome and primary fibromyalgia syndrome as recognized by GPs. Family Practice, 1999, 16, 6, 602-604.

Pheley, AM., Melby, D., Schenck, C., Mandel, J and Peterson PK. Can we predict recovery in chronic fatigue syndrome? Minnesota Medicine 1999, 82, 11, 52-56.

Longitudinal study which reports a recovery rate of 12%.  Less severity at the initial clinic visit was associated with a positive prognosis.

MEETING ABSTRACTS

Christodoulou, C., DeLuca, J., Rosenstein, E., Kramer, N., Mills, D., Cifelli, AF and Natelson, BH. Acquisition, storage and retrieval of verbal material in chronic fatigue subjects with and without psychiatric co morbidity. Archives of Clinical Neuropsychology, 1999, 14, 8, 652.

This abstract summarises the findings of a study involving 51 patients with CFS, of whom 22 had a psychiatric illness since onset and 29 did not. They were compared with two control groups: 30 healthy persons and 19 with rheumatoid arthritis. Verbal memory was assessed using a word list learning task. Recall and recognition  were tested after 30 and 90 minute delays.

The two CFS groups required more trials to learn the word list than the healthy controls.  During recall, the CFS patients without psychiatric disorders performed more poorly than the healthy controls. There were no significant group differences for recognition.  The findings indicate that verbal memory impairment in CFS results from deficient acquisition.  Those without psychiatric disorders also exhibited deficient retrieval from long term storage (as evidenced  by the impaired recall in the face of intact recognition.)

Crofford, LJ., Engelberg, NC., Korzan, A., Brucksch, CB., McClure, LA., Brown, MB and Demitrack, MA.  Circadian analysis of ACTH and cortisol in patients with fibromyalgia and chronic fatigue syndrome. Arthritis and Rheumatism, 1999, 42, (9 SUPPL), S344.

This study assessed levels of ACTH and cortisol for 24 hours in 15 patients with CFS, 11 with fibromyalgia (FM), 11 with both and a number of matched controls.

The patterns of the patients with CFS and FM were different from those seen in melancholic depression. Alterations included low peak ACTH levels with delayed decline of cortisol from peak levels. These changes resulted in an overall blunted variation of both ACTH and cortisol over time for all patient groups.

Crofford, LJ., Young, EA., Engleberg, NC., Masterson, LD., Dawson, EC., Spindler, K., McClure, LA., Brown, MB and Korszun, A  Luteal phase hypothalamic-pituitary-gonadal axis function in women with fibromyalgia or chronic fatigue syndrome. Arthritis and Rheumatism 1999, 42 (9 SUPPL), S151.

This study measured levels of oestradiol, FSH, LH and progesterone in nine women with FM and eight women with CFS during the follicular phase. No differences were found between these women and a group of healthy controls.

White, KP., Speechley, M., Harth, M and Ostbye, T. Co-existence of chronic fatigue syndrome (CFS) among adults with fibromyalgia (FM) identified in a general population survey. Arthritis and Rheumatism, 1999, 42 (9 SUPPL), S341.

This study found that 58% of women with FM and 80% of men also fulfilled the CDC '88 criteria for CFS. People with FM and CFS reported worse overall health, a worse course, more non-CFS symptoms and greater disease impact than those with FM alone.

White, KP., Speechley, M., Harth, M and Ostbye, T. A study of fibromylagia-chronic fatigue syndrome (FM-CFS) overlap in the general population. Arthritis and Rheumatism, 1999, 42 (9 SUPPL), S153.

This report notes that adults meeting criteria for both FM and CFS appear to have worse health and functioning than people meeting either criteria alone.

MISCELLANEOUS

Aaron, LA, Burke, MM and Buchwald, D.  Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder.  Archives of Internal Medicine, 2000, 160, 2, 221-227.

Ali, M and Ali, O. Oxidative coagulopathy in fibromyalgia and chronic fatigue syndrome. American Journal of Clinical Pathology, 1999, 4, 566-567.

Baschetti, R. and Romano, TJ. Letters plus reply by Goldenberg, DL. Fibromyalgia, chronic fatigue syndrome, and Addison Disease. Archives of Internal Medicine, 1999, 159, 20, 2481.

Bland, M. Fatigue and psychological distress. Statistics are improbable. British Medical Journal, 2000, 320, 515-516.

Letter noting an error in the statistics presented by Pawlikowska et al (ibid, 1994, 308, 763). With reply by Chalder and Wessely.

Bounous G and Molson, J. Competition for glutathione precursors between the immune system and the skeletal muscle: pathogenesis of chronic fatigue syndrome. Medical Hypotheses, 1999, 53, 4, 347-349.

Buchwald, D., Herrell, R., Ashton, S., Belcourt, M., Schmaling, K and Goldberg, J.  The chronic fatigue twin registry: method of construction, composition, and zygotic assignment. Twin Research, 1999, 2, 3, 203-211.

Chia, JKS and Chia, LY. Chronic Chlamydia pneumoniae infection: a treatable cause of chronic fatigue syndrome. Clinical Infectious Diseases, 1999, 29, 2, 452-453.

Dunstan, RH., McGregor, NR., Watkins, JA., Donohoe, M., Roberts, TK.. Butt, HL., Murdoch, RN and Taylor, WG.  Changes in plasma lipid homeostasis observed in chronic fatigue syndrome patients. Journal of Nutritional & Environmental Medicine, 1999, 9, 267-279.

Jason, LA., Tryon, WW., Taylor, RR., King, C., Frankenberry, EL and Jordan, KM. Monitoring and assessing symptoms of chronic fatigue syndrome: use of time series regression. Psychological Reports, 1999, 85, 1, 121-130.

Case study where a patient rated fatigue, perceived energy, expended energy (physical and mental) and affect, every waking hour for six days and at the end of the day for five months. The data presented in this article suggest that CFS is a syndrome involving reductions in absolute energy rather than a disorder of perception.

Naranch, K., Singer, A., Gaumond, E., Khine, A., Velarde, A., Clauw, D and Baraniuk, JN. Dyspnea in fibromyalgia (FM) and chronic fatigue syndrome. American Journal of Respiratory and Critical Care Medicine, 1999, 159, (3 SUPPL), A763.

Nasralla, M., Haier, J and Nicolson, GL. Multiple mycoplasmal infections detected in blood of patients with chronic fatigue syndrome and/or fibromyalgia syndrome. European Journal of Clinical Microbiology & Infectious Diseases, 1999, 18, 12, 859-865.

A total of 91 patients diagnosed with CFS/fibromyalgia syndrome and with a positive test for any mycoplasmal infection were investigated for the presence of Mycoplasma fermentans, Mycoplasma pneumoniae, Mycoplasma hominis and Mycoplasma penetrans in blood using forensic polymerase chain reaction. Among these patients, infections were detected with Mycoplasma pneumoniae (54/91), Mycoplasma fermentans (44/91), Mycoplasma hominis (28/91) and Mycoplasma penetrans (18/91). Multiple mycoplasmal infections were found in 48 of 91 patients, with double infections being detected in 30.8% and triple infections in 22%, but only when one of the species was Mycoplasma pneumoniae or Mycoplasma fermentans. Patients infected with more than one mycoplasmal species generally had a longer history of illness, suggesting that they may have contracted additional mycoplasmal infections with time.

Rowe, PC., Barron, DF., Calkins, H., Maumenee, IH., Tong, PY and Geraghty, MT. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers‑Danlos syndrome. Journal of Pediatrics, 1999, 135, 4, 494-499.

Takahashi, Y., Sano, A and Matsuo, M.  An effective "transluminal balloon angioplasty" therapy for pediatric chronic fatigue syndrome with nutcracker phenomenon. Clinical Nephrology, 2000, 53, 77-78.

Wagenmakers, AJM  Chronic fatigue syndrome: the physiology of people on the low end of the spectrum of physical activity? (Editorial). Clinical Science, 1999, 97, 5, 611-613. Correction: Clinical Science, 1999, 97, 6, 719.

Uter, W. Chronic fatigue syndrome and nickel allergy. Contact Dermatitis, 2000, 42, 1, 56.

Various. Functional somatic syndromes. Annals of Internal Medicine, 2000, 132, 327-330.

Letters criticising the review by Barsky and Borus, with particular reference to their discussion of CFS and Gulf War Syndrome.

Hedrick notes that the authors left out articles which were inconsistent with their arguments and "inaccurately portrayed" some of the research they did include.  In her view, this paper will inevitably mislead internists dealing with patients who have poorly understood illnesses. McSherry writes that the article offered cogent arguments relating to conditions such as candidiasis, hypoglycaemia, sick building syndrome and mitral valve prolapse. However, he was not impressed with the view that conditions are less common when they are not covered by health insurance.  "I've never been able to determine how secondary gains that include financial hardship, social isolation, and reduced quality of life can perpetuate illness behavior and offer anything other than a spur to recovery".

K. Cleminger challenges the reasoning that CFS had "enough in common" with other syndromes for them to be lumped together. He asks "since when was 'enough' a suitable quantification to pass peer review? What constitutes 'enough'?" A. Cleminger, a physician and father of a patient with CFS found the article "most upsetting", and asks why the authors placed such credence on the writings of a professor of English [Showalter]?. Goudsmit questions the authors' assumption that CFS is a single entity, with a single cause, and an identical set of beliefs and behaviors among patients. She also notes the selective discussion of the literature, plus the generalisations, oversimplification and "theory-led blindness to individual differences... Would such obvious bias be acceptable in obstetrics or oncology?"

Heard describes her approach to her illness which is totally at odds with the views expressed by the authors, while Albrecht challenges the way in which the evidence was presented. English focuses on the authors' definition of FSS and lists some of the evidence of pathology found in CFS. "The burden of proof is on the authors to show 'no demonstrable tissue abnormality'. They do not. Subsequent discussion on the CFS lacks logical foundation.  Even if there were normal histologic findings in the CFS, the authors would still be on shaky ground... A simple 'I don't know' would have been better than specious speculation. The authors confuse absence of evidence with evidence of absence... Absence of evidence may reflect insufficient research, inadequate technology, poor methods, flawed paradigms, closed minds, or lack of clinical experience; for example, in 1980, there was no clear evidence that AIDS was viral - blood products were considered 'safe'".  He ends by stressing the considerable suffering associated with CFS and fibromyalgia. "We must not add to that suffering by trivializing patients with 'functional' labels. Marginal care inevitably ensues".

Kurt writes as a medical toxicologist and describes some of the findings in relation to Gulf War Syndrome which contradict the views of the authors.

In response, Barsky and Borus repeat the main point of their report, "which was that psychosocial factors and symptom amplifiers compound, perpetuate, and intensify symptoms that result from a variety of causes and that they make symptom relief more difficult to attain. We specifically did not assert that these psychosocial factors initiate or are necessarily their primary cause... However, once patients are symptomatic, then beliefs, expectations, the sick role, and psychological distress become important in amplifying, maintaining, and perpetuating these symptoms and heightening the disability they engender." They refute the criticisms that they trivialised these illnesses, alleging that "these patients are not malingering or feigning illness, nor do they wish to be ill or prefer to remain so". They maintain that the entire thrust of their paper was "to take their suffering seriously". They also claim that the same psychosocial factors operate in some medical conditions, such as ischemic heart disease and suggest that there may well be a subgroup of patients within each FSS who "have a medical condition that is not yet adequately understood or diagnosable by using current techniques".

[Ed. note: It is unclear why these authors do not accept SPECT, MRI and other measures referred to in the letters as "current techniques" or why they refuse to take all the evidence of ongoing pathology into account when considering the classification of illness as 'medical' or 'functional'. Suffice to say, medical and psychosocial factors are not mutually exclusive, but that's not the issue here. We know that psychosocial variables influence the experiences of some patients. However, is that a good enough reason to reclassify a condition as 'functional'? Similarly, is evidence of psychological complications in a subset more important and reliable than evidence of pathology?  Since when?  Finally, it would be interesting to know how the authors justify their comment about trivialisation given their description of FSS as "benign symptoms and self-limited conditions".]

REVIEWS

Breau, LM., McGrath, PJ and Ju, LH. Review of juvenile primary fibromyalgia and chronic fatigue syndrome.  Journal of Developmental and Behavioral Pediatrics, 1999, 20, 4, 278-288.

Evengard, B., Schacterle, RS and Komaroff, AL.  Chronic fatigue syndrome: new insights and old ignorance. Journal of Internal Medicine, 1999, 246, 5, 455-469.

Johnson, SK., DeLuca, J and Natelson, BH. Chronic fatigue syndrome: Reviewing the research findings. Annals of Behavioral Medicine, 1999, 21, 3, 258-271.

Lloyd, AR., Hickie, I and Peterson, PK.  Chronic fatigue syndrome: current concepts of pathogenesis and treatment. Current Clinical Topics in Infectious Diseases, 1999, 19, 135-159.

[Ed. note: The authors accept that there are subpopulations with "potentially divergent disease processes", but they seem to ignore this in the discussion of graded exercise. There is also some confusion as to their own approach. Graded activity involves increasing levels according to a predetermined plan and irrespective of fatigue. Patients are allowed to stay at the same level when unwell, but most articles discourage them from stopping. However, the authors refer to stopping tasks "before they produce an exacerbation of symptoms", which suggests they advocate some kind of pacing, rather than the rigid graded activity programmes described in the literature (cf. Fulcher and White 1997).]

GENERAL FATIGUE

Hartz, AJ., Kuhn, EM., Bentler, SE., Levine, PH and London, R. Prognostic factors for persons with idiopathic chronic fatigue.  Archives of Family Medicine, 1999, 8, 6, 495-501.

PUBLICATIONS ON OTHER DISORDERS

Eaton, KK. Do yeasts play any part in "Candida" (fungal-type dysbiosis)?  Discussion Paper. Journal of Nutritional and Environmental Health, 1999, 9, 323-327.

Critical discussion of the evidence implicating Candida in the condition currently termed fungal-type dysbiosis.

Hall, S and Marteau, T. Attributions and adjustment to serious illness: a systematic review of the literature. Proceedings of the British Psychological Society, 2000, 8, 1, 16.

Abstract. It is generally assumed that behavioural self-blame is adaptive and that blaming others is maladaptive. The authors reviewed the published literature on attributions for serious illnesses and outcomes. Eighty-three per cent of the studies showed no association between attributions and outcomes, two per cent were associated with better outcomes and 15% with poorer outcomes. "The hypotheses that behavioural self-blame is adaptive and blaming others is maladaptive were not upheld. No attribution was strongly associated with better outcomes. Characterological self-blame was most often associated with poorer outcomes..."

[Ed. note: Proponents of the CBT model have suggested that attributions play a major role in CFS, and that blaming physical disease is associated with poor outcome. However, there are currently no studies among well-defined patients with CFS which supports this thesis. Moreover, it is not valid to cite the research by Sharpe et al (1992) in this regard. This revealed that patients (with fatigue) who remained unwell over the course of their study reported both external attributions and an intolerance to alcohol at follow-up. The problem is that since the attributions were not measured at the start of the study, one can not conclude that the external attributions were responsible for the chronicity of the fatigue. Another factor to take into account is the evidence of ongoing pathology, indicating that for many cases of CFS, such attributions are correct. This would also explain the link between disease conviction and the Karnofsky score reported by Wilson et al 1994. The beliefs which have a stronger relationship with outcome relate to the effects of exercise rather than aetiology.]

Heim, C., Ehlert, U and Hellhammer, DH.  The potential role of hypocortisolism in the pathophysiology of stress-related bodily disorders. Psychoneuroendocrinology, 2000, 25, 1, 1-35.

Ziem, GE. Profile of patients with chemical injury and sensitivity, part II. International Journal of Toxicology, 1999, 18, 6, 401-409.

Interesting article on multiple chemical sensitivity and its relationship with CFS.

ON REQUEST

(Individuals can request an evaluation of specific articles by writing to the address below).

Reid, S., Chalder, T., Cleare, A., Hotopf, M and Wessely, S.  Chronic fatigue syndrome. Clinical Evidence, 1999, 2, 397-405. See also BMJ, 2000, 320, 292-296 (Essentially the same text with an additional section on NADH and conclusions).

This review focuses on the treatment of CFS. Given the constraints of space, the discussion below is limited to observations which readers might like to consider when assessing the article.

The first thing to note is that the authors accept the difference between the Oxford and CDC criteria, but do not always allude to the heterogeneity of the population where relevant (e.g. in trials of CBT and/or graded exercise). Also of interest is that the section on CBT does not mention the trial by Friedberg and Krupp (1994), although it was well-controlled and used standard diagnostic criteria as well as valid measures. (The findings revealed significant improvements but only for patients with depression.) Conversely, the review overlooks the flaws of the trial by Sharpe et al (e.g. the high percentage of patients with psychiatric disorders, the lack of a valid measure for fatigue, and the noteworthy differences between the groups at baseline. For instance, the treatment group spent twice as long in bed as the controls, despite having almost identical scores for fatigue and disability. Also, far fewer of the treated patients worked - 4 versus 15 - so the increase following treatment may have reflected opportunity or encouragement as much as ability!)

I would also challenge some of the criticisms directed at the Australian study. For instance, the authors claim that there were "no attempts at cognitive reappraisals" and implied that the practitioners were not "highly skilled cognitive behavioural therapists".  However, this is difficult to substantiate given the researchers' response to a published letter by two of the authors (Chalder, Wessely), in which they confirmed that "patients' beliefs regarding key attitudes such as the possible effects of physical activity were challenged..." (Hickie at al, 1995).

In relation to the criticism about the expertise of the therapists, the researchers noted that the treatment was designed by a psychiatrist who had "extensive experience with patients with CFS and with cognitive-behavioural approaches to the treatment of depression. The treatment was administered by experienced psychiatrists". Given this response, it's hard to understand why Reid et al chose to repeat this allegation at this time. Leaving aside the issue relating to the evaluation of skills in this case, are the authors suggesting that CBT is only effective if provided by highly skilled behaviour therapists? If so, what's the evidence that it's not effective in the hands of appropriately trained, knowledgeable and sympathetic psychologists and psychiatrists?

The likeliest explanation for the disappointing results is that the Australian sample included a greater percentage of pure, post-infectious cases than the successful British trials (which selected a broadly-defined sample and often included people with irrational beliefs and poor coping strategies). This may also explain two other negative reports, neither of which are mentioned.

Based on the evidence, the authors might have concluded that CBT is beneficial for people with broadly-defined CFS, complicated by mood disorders and/or phobic avoidance (e.g. Friedberg 1999). However, a blanket recommendation covering everyone with CFS is hard to justify. For instance, there is still no published study which shows it to be effective for strictly-defined or infection-related CFS without psychological complications.

Regarding exercise, the review overlooks the methodological flaws in the studies described, e.g. the focus on fatigue but not somatic symptoms, the lack of data on pure post-infectious cases etc. Moreover, the authors state that they were unable to find any evidence of adverse effects of exercise, thus ignoring all the reports to the contrary (e.g. Lapp 1997). Elsewhere they point to "observational evidence" e.g. that "prolonged inactivity may perpetuate or worsen fatigue".  However, they make no reference to studies which actually measured activity levels (e.g. Vercoulen et al 1997 etc.) and found that their 'observation' isn't relevant to the majority of patients with CFS. In short, the research indicates that most of those affected remain ambulant and pace themselves, operating at or near their activity ceiling (cf. research by Jason et al). Only a tiny minority may be inactive for long periods of time and usually this is linked to the severity of symptoms rather than fear (Bazelmans et al, Conference Report 1999). Such information is relevant and should have been considered if one is claiming an objective, evidence-based approach.

The section on immunotherapy missed a positive study using ganciclovir, presumably because it wasn't controlled, though that cannot explain the omission of the trials on Ampligen. The end result was an emphasis on the negative reports. The comments on treatments other than CBT, exercise, rest and immunotherapy seem to be consistent with the literature.

In my view, this is a biased and misleading report reflecting a selective assessment of the relevant research and a clear preference for the cognitive-behavioural explanation for CFS.  It's certainly not a dispassionate account based on 'best evidence'.

The references can be found online.

Price, JR and Couper, J. Cognitive behaviour therapy for chronic fatigue syndrome in adults (Cochrane Review). In: The Cochrane Library, Issue 4, 1999. Oxford: Update Software.

The authors selected just three studies for evaluation: Sharpe et al 1996, Deale et al 1997, and Lloyd et al 1993. Amongst the excluded trials were Friedberg and Krupp 1994.

The authors conclude that CBT "appears an effective and acceptable treatment for adult out-patients with chronic fatigue syndrome."  However, elsewhere they state: "there is currently no evidence of high quality that the complex intervention that is CBT is any more effective than simpler interventions, such as the provision of a programme of graded exercise and activity".

In my opinion, this review lacks balance and objectivity, and reveals a lack of familiarity with the literature as well as some of the measures. It overlooks major flaws in the studies selected for assessment, especially the two which support the conclusion that CBT is "effective" across the board. As I've noted above, blanket recommendations for CFS are not supported by the evidence.

Space does not permit me to discuss these criticisms in detail but here are just a few illustrations of the authors' bias. For example, experienced clinicians and researchers know that the Oxford and CDC '94 criteria (Sharpe et al, Deale et al) select a heterogeneous sample, often including patients with psychological problems which are known to respond to CBT. Instead of mentioning this, they suggested that certain psychiatric disorders were excluded. This is misleading, given that Deale et al only excluded people with somatisation disorder or severe melancholic depression. Many of their patients, like those of Sharpe et al, may have been suffering from chronic stress, anxiety, phobic avoidance, personality problems, poor coping etc (cf. Surawy et al 1995).  It's also interesting that only 57% of Deale et al's CBT group attributed their illness to a physical cause (NB: compared to 73% of the controls).

As I've noted before, there is evidence (from all the descriptions of the samples), that Sharpe et al actually excluded people with ME/post viral fatigue who had 'sensible' beliefs and coping strategies. Indeed, the researchers have never acknowledged (publicly) that they see, let alone study or treat individuals with CFS uncomplicated by unhelpful behaviours and beliefs.  Although the focus on 'poor copers' was not made explicit in the study itself, it did reveal that the treatment group had modest levels of disability yet spent an average of 3.3 days in bed.  In my opinion, an experienced, independent referee would have been aware of the correspondence which followed the publication of Sharpe et al, plus the evaluation of this paper elsewhere. They would therefore have known about the researchers' 'interest' in what many would regard as an atypical subset (cf. Friedberg 1999), and could have advised the authors accordingly.

The only study of the three which failed to show the superiority of CBT selected a more homogeneous population, resembling post-viral syndrome/ME.  This was not mentioned. In fact, the authors claimed that this study used criteria which were "less rigorous" than the Oxford ones (p. 3). That's inaccurate and shows a serious lack of attention to detail.

Regarding the measures, it should be noted that Sharpe et al included people with a Karnofsky score of 78, where the definition of a successful outcome was a score of 80 or an improvement of 10 points. No subject scored below 60 at the start of the trial and the median was 72 (where 80+ is 'normal'). In other words, these were not the most severely disabled group (cf. Gibbons et al, BMJ, 1996, 312, 1096). However, the authors claimed that there's no evidence supporting the use of CBT for 'milder' forms of CFS.

Another relevant point which they might have considered is that Lloyd et al was the only study to measure relevant somatic symptoms and immune function. After all, if people are claiming that CBT and/or graded activity is an effective treatment for the illness as a whole, they should assess the illness as a whole, not just anxiety, depression and fatigue.

Regarding the use of relaxation therapy as a control intervention (cf. Deale et al), it is interesting that 85% of the group rated it as 'useful' or 'very useful' when 69% rated themselves as unchanged and 50% were dissatisfied with outcome. These discrepancies suggest the influence of demand characteristics or another confounding factor, thus undermining the reliability of the results. Finally, the lack of randomisation may have been a reason to exclude Friedberg and Krupp, but this was an otherwise sound study. Its findings deserved to be mentioned; after all, this review (on CBT) included Fulcher and White's study (which did not assess CBT).

An update to the article should include the latest follow-up report by Sharpe (Oct. 1999), noting that the difference between treated and untreated groups has now disappeared.

In conclusion, this is a misleading, largely opinion-based evaluation of the relevant literature.  It's an unreliable document which should have been assessed before publication by an experienced, independent referee. There's certainly no support for the authors' statement that their conclusion about CBT is based on "convincing evidence".

Comments by Dr. Ellen Goudsmit.

[Ed. note: It may be relevant to mention the following: Dr. Goudsmit trained as a behaviour therapist while studying psychotherapy at the University of Amsterdam. Dr. Price is based at the Dept. of Psychiatry, Oxford University. Given his colleagues' very strong views on the subject, it may be difficult for him to publicly express doubts about CBT.  An updated version of the Cochrane review is due to be published in the autumn.]

Further information on CBT for CFS can be found online.

• The opinions expressed are those of the author and do not necessarily reflect the views of the editorial team.

• This issue was compiled by Dr. EM Goudsmit, Dr. A. Macintyre and Mrs S. Howes. We gratefully acknowledge the help and support from Dr. C. Shepherd, M. Sullivan and Mr. D. Axford. Sources used include ISI Current Contents, ISI Personal Alert, Co-Cure and Medline. This Medical Update is funded by donations.

Disclosure

This publication aims to provide factually accurate and reliable information on chronic fatigue syndromes to clinicians and researchers around the world. It is envisaged as a supplement to the British Library Quarterly Medline Updates. Articles or reports which in the editors' opinion make a significant contribution to the literature, or which are interesting in other ways, will be summarised. Other publications are listed and readers are directed to the British Library's Update for the authors' abstracts.

None of the editors work for or receive payment from pharmaceutical companies as this may undermine editorial independence and objectivity. Summaries are written by qualified health care professionals and checked for accuracy and fairness by experienced physicians, all of whom are specialists in this field. Editorial notes are primarily aimed at identifying and correcting erroneous or misleading information, and occasionally may alert readers to relevant facts which might further aid their understanding of the subject in question.

Our sole motivation is a desire to provide reliable information, although we also wish to make colleagues aware of biased and prejudiced publications which undermine the scientific process and may cause harm to patients. Articles including personal opinions, e.g. as in the book reviews, will be clearly marked.

E-mail:

ellengoudsmit@hotmail.com or david.axford@virgin.net

Copyright EM. Goudsmit 2000. ©
Psychologist/Archivist, London.
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