ME and CFS

Capita Selecta 1998

Quick Find Immunology Neurology Physiology, Neurophysiology & Neuroendocrinology Psychiatry, Psychology & Neuropsychology Therapeutics Miscellaneous

IMMUNOLOGY

Conti, F., Pittoni, V., Sacerdote, P., Priori, R., Meroni, PL and Valesini, G. Decreased immunoreactive beta-endorphin in mononuclear leucocytes from patients with chronic fatigue syndrome. Clinical and Experimental Rheumatology, 1998, 16, 6, 729-732.

This study involved 16 patients with CFS (CDC criteria '94, 11 with post-exertional malaise) and 10 healthy controls. Beta-endorphin concentrations were measured in peripheral blood mononuclear cells (PBMC) by radioimmunoassay performed with antibodies specific for the C-terminal portion of human beta-endorphin.

Beta-endorphin concentrations in the PBMC of CFS patients were significantly lower (p<0.001) than in the healthy subjects (mean 8.5 vs. 42.6).

This finding may reflect the condition of chronic immune activation in CFS that has been reported in previous investigations. "Beta-endorphin concentrations in PBMC seem to mirror the central nervous system homeostasis of the opioid. Therefore, we would postulate that the fatigue and weakness typical of CFS could be related to low beta-endorphin concentrations at the central nervous system level."

Hassan, IS., Bannister, BA., Akbar, A., Weir, W and Bofill, M. A study of the immunology of the chronic fatigue syndrome: correlation of immunologic parameters to health dysfunction. Clinical Immunology and Immunopathology, 1998, 87, 1, 60-67.

Surface and intracellular immunological and apoptotic markers and functional lymphocyte assays after stimulation with anti-CD3/anti-CD28 antibodies or phytohemagglutinin (PHA) were studied in 44 patients with CFS (Oxford criteria but excluding the severely affected) and 20 healthy controls. The results were then correlated with the scores on the Medical Outcomes Study Short Form-36 (SF-36) and the general health questionnaire (GHQ-28), which detects psychological distress.

The patients had sig-nificantly increased mean fluorescence intensity read-ings of HLA-DR in CD4 and CD8 cells (p<0.05). Expression of the costimulatory receptor CD28 in CD8 cells was significantly reduced (also seen in chronic viral infections e.g. HIV), and the apoptosis repressor ratio of bcl-2/bax in both CD4 and CD8 was increased in patients (p<0.05). The patients with increased HLA-DR expression had significantly lower SF-36 total scores, worse body pains, and poorer gen-eral health perception and physical functioning scores. Increased spontaneous lymphocyte proliferation was associated with poor general health percep-tion. PHA proliferative responses were lower in pa-tients with poor emotional and mental health scores, and the anti-CD3/anti-CD28 response was low in those with low general health perception scores. Higher spontaneous proliferation and reduced PHA responses correlated with higher GHQ scores. Similarly, GHQ scores were significantly higher, indicating worse mental health, in those with lower total SF-36 scores and worse general and mental health scores on the SF-36 questionnaire. Finally, higher expression of the costimulatory molecule CD28 correlated with higher total SF-36 scores, general health perception and social functioning scores, and with lower role limitation due to physical health.

The increased expression of class II antigens and the reduced expression of the costimu-latory receptor CD28, which is a marker of terminally differentiated cells, lend further support to the concept of immunoactivation of T-lymphocytes in CFS and may be consistent with the notion of a viral aetiopatho-genesis in the illness. The in-creased expression of the apoptosis repressor protein bcl-2 is also significant, since it may contribute to enhanced survival of activated lymphocytes. The demonstrated changes in different immunological parameters, each of which correlated with particular aspects of disease symptomatology, is equally noteworthy.

Levine, PH., Whiteside, TL., Friberg, D., Bryant, J., Colclough, G and Herberman, RB. Dysfunction of natural killer activity in a family with chronic fatigue syndrome. Clinical Immunology and Immunopathology, 1998, 88, 1, 96-104.

A family was identified with 5 of 6 siblings and 3 other immediate family members who had developed CFS (CDC criteria '88 and '94) as adults. Sixty-eight blood samples were obtained over a period of 2 years from 20 family members (8 affected, 12 unaffected) and 8 normal controls. All blood samples were tested for NK activity and for the number of circulating CD3-CD56+ and CD3-CD16+.

The NK activity of the 8 affected immediate family members was significantly lower (p=0.006) than that of the concurrently tested normal controls. The results for unaffected family members were intermediate between these two groups, and there was no significant difference between the unaffected family members and cases. No differences were seen between the three groups in terms of the absolute number of CD3-CD56+ or CD3-CD16+ lymphocytes in the peripheral blood.

Familial CFS was associated with persistently low NK activity, which was documented in 6/8 cases and in 4/12 unaffected family members. In the family with 5 of 6 siblings who had documented CFS, 2 of their offspring had paediatric malignancies. There was also a lower CD4+/CD8+ ratio in the patients with CFS and their families compared to the normal controls. This could be attributed to the higher absolute number of CD8+ cells.

"Low NK activity in this family may be a result of a genetically determined immunologic abnormality predisposing to CFS and cancer."

NEUROLOGY

Richardson, J and Costa, DC. Relationship between SPECT scans and buspirone tests in patients with ME/CFS. Journal of Chronic Fatigue Syndrome, 1998, 4, 3, 23-38.

This study involved 39 patients with CFS (Oxford and CDC criteria) who also met criteria for ME/CFS. Three suffered from epilepsy and some were recovering from their fatigue syndrome. None had a psychiatric disorder. Tests included SPECT plus cortisol and prolactin studies after buspirone.

There were greater rises in prolactin levels in the CFS patients compared to the controls (details published elsewhere). The SPECT scans revealed that all patients had hypoperfusion in some area of the brain; 62% in the brain stem and 51% in the caudate nuclei. There was no hypoperfusion in the visual cortical areas.

According to the researchers, the findings provide "actual evidence of neurological dysfunction".

Tirelli, U., Chierichetti, F., Tavio, M., Simonelli, C., Bianchin, G., Zanco, P and Ferlin, G. Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data. American Journal of Medicine, 1998, 105, 3A, 54s-58s.

In this article, the researchers describe the results from high resolution PET scans on 18 patients with CFS (CDC criteria), 6 patients with major depression (drug free) and 6 healthy controls. None of the CFS patients had a psychiatric disorder and none were taking any medication at the time of testing.

The PET images examined 22 cortical and subcortical areas. PET is better than SPECT at detecting small structures such as the brain stem.

The scans revealed significantly reduced glucose metabolism in the brainstem of patients with CFS compared with the depressed (p<.009) and healthy controls (p<.013). The area particularly affected in the brainstem was the pons. There was also significant hypometabolism in the right mediofrontal cortex in the CFS group compared with the healthy controls (p<.010).

This research is consistent with the findings of Costa et al (QJM, 1995, 88, 767) using SPECT. The hypometabolism of the brainstem has not been documented in any psychiatric disorder assessed to date.

PHYSIOLOGY, NEUROPHYSIOLOGY AND NEUROENDOCRINOLOGY

Castell, LM., Phoenix, J., Edwards, RHT and Newsholme, EA. Plasma amino acid measurement in exercise-related chronic fatigue syndrome. Journal of Physiology, 1998, 509 (SP ISS), 206.

This short article reports on plasma concentrations of free tryptophan, branched chain amino-acids (BCAA) and the ratio of free tryptophan/BCAA before, during and after exercise (on a bicycle ergometer). Subjects were 10 patients with CFS (not defined) and 10 sedentary, age and gender matched controls. No patient took anti-depressants.

The main findings were that baseline free tryptophan levels were higher in patients than in controls (p<.05) but that the increase in those levels during and immediately after exercise in the controls was not seen in patients. There were no changes in plasma BCAA levels in either group. Finally, the plasma concentration ratio of tryptophan/BCAA was 31% higher in the patients compared with the controls and did not change during exercise.

"This, together with the abnormally high baseline level of free tryptophan in the CFS patients, might indicate increased levels of 5-HT leading to fatigue at rest. Alternatively, any involvement of the serotonergic system in chronic fatigue may be in terms of increased brain 5-HT receptor sensitivity, such as that observed by Cleare et al" (J. Affect. Disord, 1995, 35, 283).

Kuratsune, H., Yamaguti, K., Lindh, G., Evengard, B., Takahashi, M., Machii, T., Matsumura, K., Takaishi, J., Kawata, S., Langstrom, B., Kanakura, Y., Kitani, T., Watanabe, Y. Low levels of serum acylcarnitine in chronic fatigue syndrome and chronic hepatitis type C, but not seen in other diseases. International Journal of Molecular Medicine, 1998, 2, 1, 51-56.

A study of 57 Swedish women with CFS (CDC criteria '88 or '94) found significantly lower serum acylcarnitine (ACR) compared to 46 healthy controls (p<0.001). Most patients had the deficiency, which was also found previously in Japanese patients and in people with chronic hepatitis C. However, it was not present in other medically ill populations such as patients with haematological malignancies, chronic pancreatitis, hypertension and diabetes. However, some people with psychiatric disorders also showed reduced serum ACR, although the mean values were not significantly different from those of the controls.

These findings indicate that serum ACR deficiency may be a characteristic of people with CFS and that it is not a local phenomenon peculiar to the Japanese. Recently, the researchers studied the ACR uptake into the brain and found this was lower in the anterior cingulate and dorsal prefrontal cortices of the CFS group (n=8) compared to the healthy controls (n=8). These regions are thought to be related to mood and the deficiency may therefore explain some of the neuropsychiatric symptoms of CFS.

ACR may have an effect as an antioxidant and be linked to the production of cytokines.

Kuratsune, H., Yamaguti, K., Sawada, M., Kodate, S., Machii, T., Kanakura, Y and Kitani, T. Dehydroepiandrosterone sulfate deficiency in chronic fatigue syndrome. International Journal of Molecular Medicine, 1998, 1, 1, 143-146.

In order to study HPA axis and endocrine function, urine samples were collected from 49 patients with CFS and 35 healthy controls and blood samples were obtained from 17 female patients and 35 controls.

Levels of cortisol and ACTH were normal in both groups. However, the patients with CFS had lower levels of serum dehydroepiandrosterone sulfate (DHEA-S) compared with the controls (p<.001) and higher levels of androstenedione (p<.001). The DHEA-S deficiency was not related to age.

Serum DHEA-S is one of the most abundantly produced hormones which are secreted from the adrenal glands, and its physiological function is thought to be a precursor of sex steroids. DHEA-S has recently been shown to have physiological properties, such as neurosteroids, which are associated with such psychophysiological phenomena as memory, stress, anxiety, sleep and depression. Therefore, the deficiency of DHEA-S might be related to the neuropsychiatric symptoms in patients with CFS. Levels of DHEA-S were lower in those patients reporting cognitive impairment and depression.

[Ed. note: DHEA is an important immune system regulator. Since it is also produced in the skin (source: Loria), fresh air and sunshine may aid recovery.]

Lane, RJM., Barrett, MC., Woodrow, D., Moss, J., Fletcher, R and Archard, LC. Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome. Journal of Neurology, Neurosurgery and Psychiatry, 1998, 64, 3, 362-367.

The aim of this study was to examine the proportions of type 1 and type 2 muscle fibres and the degree of muscle fibre atrophy and hypertrophy in patients with CFS in relation to lactate responses to exercise, and to determine to what extent any abnormalities found might be due to inactivity.

Quadriceps needle muscle biopsies were obtained from 105 patients with CFS (Oxford criteria) and the proportions of type 1 and 2 fibres and fibre atrophy and hypertrophy factors were determined from histochemical preparations, using a semiautomated image analysis system. Forty one randomly selected biopsies were also examined by electron microscopy. Lactate responses to exercise were measured in the subanaerobic threshold exercise test (SATET).

Inactivity would be expected to result in a shift to type 2 fibre predominance and fibre atrophy, but type 1 predominance (23%) was more common than type 2 predominance (3%), and fibre atrophy was found in only 10.4% of cases. Of the total sample, 37% had abnormal lactate responses to exercise. Patients with increased lactate responses to exercise had significantly fewer type 1 muscle fibres (p<0.043 males, p<0.0003 females), but there was no evidence that this group was less active than the patients with normal lactate responses. No significant ultrastructural abnormalities were found.

The researchers conclude that muscle histometry in patients with CFS generally did not show the changes expected as a result of inactivity. Patients with abnormal lactate responses to exercise had a significantly lower proportion of mitochondria rich type 1 muscle fibres.

Lane, RJM., Barrett, MC., Taylor, DJ., Kemp, GJ and Lodi, R. Heterogeneity in chronic fatigue syndrome: evidence from magnetic resonance spectroscopy of muscle. Neuromuscular Disorders, 1998, 8, 3-4, 204-209.

It has been shown previously that some patients with CFS show an abnormal increase in plasma lactate following a short period of moderate exercise, in the sub-anaerobic threshold exercise test (SATET). This cannot be explained satisfactorily by the effects of 'inactivity' or 'deconditioning', and patients with abnormal lactate responses to exercise (SATET +ve) have been found to have significantly fewer Type 1 muscle fibres in quadriceps biopsies than SATET -ve patients. The researchers performed phosphorus magnetic resonance spectroscopy on the forearm muscles of 10 SATET +ve patients with CFS (Oxford criteria), 9 SATET -ve patients with CFS and 13 sedentary volunteers.

There were no differences in resting spectra between these groups but at the end of the exercise, the intracellular pH in the SATET +ve patients was significantly lower than in both the SATET -ve cases and controls (p< 0.03). The SATET +ve patients also showed a significantly lower ATP synthesis rate during recovery (p<0.01), indicating impaired mitochondrial oxidative phosphorylation.

"These observations support other evidence which indicates that CFS is a heterogeneous disorder, and confirms the view that some CFS patients have a peripheral component to their fatigue."

Saggini, R., Pizzigallo, E., Vecchiet, J., Macellari, V and Giacomozzi, C. Alteration of spatial-temporal parameters of gait in chronic fatigue syndrome patients. Journal of Neurological Science, 1998, 154, 18-25.

Information relating to spatial and temporal parameters of gait was collected from 12 patients with CFS (criteria unclear) and compared with the reference data from 596 healthy individuals.

The results showed that there were significant differences between the two groups. The abnormalities were present from the beginning of the gait analysis, indicating that they were unlikely to be caused by increasing fatigue. Indeed, they generally improved with time, suggesting the possible influence of deconditioning. There were "greater significant motor alterations in those patients with a severe neuropsychological deficiency".

Sisto, SA., Tapp, WN., LaManca, JJ., Ling, W., Korn, LR., Nelson, AJ and Natelson, BH. Physical activity before and after exercise in women with chronic fatigue syndrome. Quarterly Journal of Medicine, 1998, 91, 7, 465-473.

The researchers measured daytime physical activity in 20 women with CFS (CDC criteria '88, moderate symptoms of <6 years duration, no premorbid psychiatric disorders), and 20 sedentary but healthy volunteers. Activity was measured for 2 weeks using a portable waist-worn vertical accelerometer.

After the first week of activity monitoring, all participants returned for a maximal treadmill test, followed by continued activity monitoring for a second week.

Prior to the exercise test, there was a significant group difference in activity levels (p<.01) with the CFS group demonstrating 15% less average activity per unit time. After exercise, the CFS patients reduced their average activity levels (10% up to a maximum of 30%), notably on days 5-7. At the same time, there was an increase in the length of the active day (13%) and in the number of daily rests (up to 26.5%). There was no group difference for total daily activities or duration of rest periods post-exercise.

"Marked exertion does produce changes in activity, but later than self-report would suggest, and they are apparently not so severe that CFS patients cannot compensate". The finding that neither total daily activity or duration of rest changed post-exercise does not support the fear avoidance model of CFS.

[Ed. note: the CDC criteria do not require the presence of post-exertional fatigue although the researchers note that many of their patients do report this symptom.]

Scott LC and Dinan, TG. Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers. Journal of Affective Disorders, 1998, 47, 1-3, 49-54.

Urinary free cortisol excretion (UFC) was measured in 21 patients with CFS (CDC criteria, 5 had comorbid depression), in 10 melancholic depressives and in 15 healthy controls.

Patients with depression had UFC values which were significantly higher than healthy comparison subjects, whereas UFC excretion of CFS patients was significantly lower than the comparison group. These findings are in keeping with currently held hypotheses of hyperactivity and hypoactivity of the hypothalamic-pituitary-adrenal (HPA) axis in depression and CFS. The subgroup of CFS patients with depression retained the profile of UFC excretion of those with CFS alone, suggesting a different pathophysiological basis for depressive symptoms in CFS.

Servatius, RJ., Tapp, WN., Bergen, MT., Pollet, CA., Drastal, SD., Tiersky, LA., Desai, P and Natelson, BH. Impaired associative learning in chronic fatigue syndrome. Neuroreport, 1998, 9, 1153-1157.

Patients with CFS report cognitive difficulties (impaired attention, memory and reasoning). The researchers tested 12 patients with CFS (CDC criteria '94) and 14 sedentary controls in protocols designed to measure sensory reactivity and acquisition of the classically conditioned eyeblink response. The latter involved pairing an unconditioned stimulus (US: airpuff) with a conditioned stimulus (CS: tone), eventually producing a conditioned response (eyeblink) if the latter occurred from 200 ms after the tone.

The patients displayed impaired acquisition of the eyeblink response. Sensitivity and responsivity to the airpuff (US) were normal. In a separate test, patients with CFS exhibited normal sensitivity and responsivity to acoustic stimuli (noise).

In the absence of sensory/motor abnormalities, the impaired acquisition of the classically conditioned eyeblink response indicates an associative deficit (i.e. impaired ability to learn the contingency between CS and US). "These data suggest organic brain dysfunction within a defined neural substrate in CFS patients."

Strickland P., Morriss R., Wearden A and Deakin B. A comparison of salivary cortisol in chronic fatigue syndrome, community depression and healthy controls. Journal of Affective Disorders, 1998, 47, 191-194.

Previous studies reporting cortisol hyposecretion in CFS may have been confounded by venepuncture, fasting and hospitalisation. In this study, morning and evening salivary cortisol were obtained on consecutive days during the first 3 days of the menstrual cycle and compared to those of 3 samples of women taking no medication and matched for age: 14 patients with CFS (Oxford criteria, 10 of whom also met criteria for mild/moderate depression); 26 community cases with current depression and 131 healthy community controls.

The mean evening cortisol was significantly lower in the CFS patients compared to the people with depression (p=0.02) and healthy controls (p=0.005). CFS patients without psychiatric disorder had significantly lower morning salivary cortisol compared to controls (p=0.009). The levels were not related to sleep disturbance or fitness.

The researchers conclude that CFS patients display cortisol hyposecretion in saliva compared to patients with depression and healthy controls. There was no assessment of chronic anxiety.

"Chronic fatigue syndrome is biochemically distinct from community depression".

Young, AH., Sharpe, M., Clements, A., Dowling, B., Hawton, KE and Cowen, PJ. Basal activity of the hypothalamic-pituitary-adrenal axis in patients with the chronic fatigue syndrome (neurasthenia) Biological Psychiatry, 1998, 43, 236-237.

Basal activity of the HPA was assessed using salivary and urinary cortisol collection over a 24-hour period in 22 patients with CFS (CDC criteria '94, mean duration 2.5 years) and neurasthenia (ICD-10). None suffered from a current depressive or anxiety disorder. Their results were compared with those from 22 sedentary, healthy controls.

The findings showed that salivary and urinary cortisol measures did not differ between CFS patients and controls. Thus basal activity of the HPA was not reduced in CFS patients.

PSYCHIATRY, PSYCHOLOGY AND NEUROPSYCHOLOGY

Christodoulou, C., DeLuca, J., Lange, G., Johnson, SK., Sisto, SA., Korn, L and Natelson, BH. Relation between neuropsychological impairment and functional disability in patients with chronic fatigue syndrome. Journal of Neurology, Neurosurgery and Psychiatry, 1998, 64, 431-434.

This study examined the relationship between neuropsychological impairment and functional disability in 53 patients with CFS (CDC criteria '88 and '92, plus additional requirements) and 32 healthy controls who did not take regular exercise. Measures included the Beck Depression Inventory (BDI), the Functional Status Questionnaire (assessing activity) and tests of verbal memory (CVLT), attention and concentration (PASAT) and visual memory (ROCF). A test score was defined as failing when it was >2 SD below the mean of the healthy controls after controlling for demographic factors. Subjects were also interviewed (Q-DIS).

Those patients with CFS with higher numbers of failing neuropsychological test scores reported significantly more days of general inactivity in the past month than those with fewer failing scores. This result remained significant even after partialling out the contribution of the presence of a comorbid axis I psychiatric episode and total BDI score. Patients with failing verbal memory scores were particularly functionally disabled compared with those with passing scores. There was no significant relationship between cognitive test results and either daily living or social activities.

The researchers conclude that the relationship between cognitive impairment and functional disability could not be explained entirely on the basis of psychiatric factors.

The associated editorial by Lambert and David (p. 430) regards cognitive impairment as mental fatigue and is largely focused on those findings which are consistent with the CBT model of CFS.

Deale, A., Chalder, T and Wessely, S. Illness beliefs and treatment outcome in chronic fatigue syndrome. Journal of Psychosomatic Research, 1998, 45, 1, 77-83.

Assessments made during a trial of CBT and relaxation (see Deale et al 1997) revealed that physical illness attributions were not associated with poor outcome in either group. There were no significant associations between causal attributions and specific beliefs about exercise, e.g. a belief in a physical illness did not lead to avoidance. Only 8% of the 60 patients reported that they "should avoid physical activity". Beliefs like 'I should avoid exercise when tired' changed particularly in the CBT group and were associated with improved outcome. However, a change in the view that 'exercise is harmful' was not associated with improvement. Changes in beliefs were not limited to the treatment group; in the controls, there was a significant reduction in the number of patients who thought that 'exercise is harmful'.

The researchers note that "the direction of causality has not been established: causal attributions and beliefs about avoidance could well be a consequence of fatigue and past experience. Patients for whom treatment was ineffective may well have had such beliefs confirmed."

The findings suggest that "causal attributions are less important than beliefs and behaviours related to avoidance in perpetuating CFS." The behavioural change may have been the key component of treatment, supporting the view that increases in activity are more important than changing beliefs.

Heijmans, MJWM. Coping and adaptive outcome in chronic fatigue syndrome: importance of illness cognitions. Journal of Psychosomatic Research, 1998, 45, 1, 39-51.

This researcher interviewed 98 patients with CFS (not defined, diagnosis by doctor, all recruited from Dutch ME Association). The results showed that the subgroup who felt they had no control over their illness, who saw little possibility for a cure and who believed their illness to have serious consequences, tended to cope with their illness in a passive way, reporting high levels of impairment and greater problems in mental health and vitality than patients who coped differently. The study also revealed that patients tended to identify several causes (mean number 9.3), although 57% mentioned physical factors in their response. The majority preferred the term ME to CFS.

In terms of its relationship to outcome, a belief in a psychological cause correlated with more mental health problems. However, a belief in control was associated with greater vitality, less physical impairment and better mental health. A belief in a biological cause was associated with fewer mental health problems but more difficulties with vitality.

A belief in controllability was associated with less cognitive-avoidant coping and more problem-focused coping. A belief in a biological cause encouraged more support-seeking but wasn't associated with avoidant coping. No coping strategy, with the exception of venting emotions, was found to be related to physical functioning.

The researcher notes that passive coping, e.g. cognitive avoidant strategies, appear to produce mental health problems and reduced social functioning. Problem-focused strategies did not predict functioning or mental health, nor did seeking social support.

[Ed. note: The findings show the variety of beliefs and coping strategies among people with CFS. They also support other research showing that a belief in biological causation is not necessarily maladaptive. The discussion section appears to be based on a selective review of the literature. The conclusions may therefore come across as rather biased towards one explanation for CFS. The findings do not support the CBT model which emphasises avoidant coping and does not recognise other adaptive strategies such as pacing, accommodating to the illness etc. (see below).]

Knussen, C and Lee, D. Chronic fatigue syndrome: symptoms, appraisal and ways of coping. British Journal of Health Psychology, 1998, 3, 111-121.

This study involved 81 patients with CFS who were recruited through support groups; 89% were diagnosed by a medical practitioner but the remainder were self-diagnosed. Measures included the Profile of Fatigue-Related Symptoms, a coping questionnaire (IMQ) and the Meaning of Illness Questionnaire which assesses appraisal (impact of illness, positive attitude etc.).

CFS was often appraised as a source of stress. Negative appraisals were associated with focusing on symptoms and less accommodation to the illness. The patients whose illness was linked to stress rather than infection reported more fatigue. Those who saw CFS as more of a threat also reported more fatigue. Optimism was negatively correlated with fatigue as well as emotional distress.

Having more symptoms was associated with seeking information, maintaining activity and less accommodating to the illness. Those who accommodated to the illness experienced fewer symptoms; they were also less likely to perceive the illness as stressful, to experience optimism and to perceive that the illness had had a less negative impact. Those with more emotional distress had less optimism and were less likely to accommodate to the illness by reducing their activities, irrespective of their symptoms of fatigue.

LaManca, JJ., Sisto, SA., DeLuca, J., Johnson, SK., Lange, G., Pareja, J., Cook, S and Natelson, BH. Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome. American Journal of Medicine, 1998, 105, 3A, 59s-65s.

This study compared 19 patients with CFS (CDC criteria '88, '92 and '94 plus significant disability, no psychiatric disorders in the 5 years prior to illness, duration <6 years) and 20 sedentary controls on a number of cognitive tests before and after exercise to exhaustion.

The cognitive tests included measures assessing speed, vigilance, and attention. Other measures included the BDI, an IQ test (NAART) and ratings for fatigue and symptom severity. The cognitive test battery was completed before, immediately after and 24 hours after exercise on a treadmill to exhaustion.

There were no significant differences on the cognitive tests prior to exercise, no differences on the IQ test and no differences in terms of aerobic fitness levels between the groups. The CFS patients were more depressed but the mean (14.7) was suggestive of mild depression only. Post-exercise, there was no effect on accuracy, but on the tests assessing rapid naming and perceptual motor speed, the CFS group were significantly impaired. The patients also reported more fatigue.

The researchers conclude that after exercise, patients with CFS demonstrated impairment in terms of the speed of information processing, though not attention. The impairment was maintained at 24 hours post-exercise.

Ray, C., Jefferies, S., Weir, W., Hayes, K., Simon, S., Akingbade, F and Marriott, P. Making sense of chronic fatigue syndrome: patients' accounts of onset. Psychology & Health, 1998, 13, 99-109.

Sixty patients with CFS (Oxford criteria plus post-exertional fatigue) were interviewed about the onset of their illness, and the factors which they felt had contributed to that onset.

Common themes in these qualitative data were episodes of infection, "doing too much" and stressful circumstances; in two-thirds of cases, accounts encompassed physical, behavioural and psychological factors. Patients described a gradual, sharp or phased onset, the latter involving a sharp onset but with a short term lifting of symptoms before worsening into chronic illness. A gradual onset was associated with longer duration of illness.

Particular themes played a different role in patients' accounts, depending upon onset pattern. With a sharp or phased onset the most common perceived trigger for the abrupt change in health status was an episode of infection, but preceding factors were often invoked to explain the effect that this had had. With a phased onset, subsequent compounding factors (typically overdoing things) were similarly cited to explain worsening and the long-term effect of the trigger. Thus, patients provided complex and dynamic accounts of illness onset, incorporating interacting factors.

Saltzstein, BJ., Wyshak, G., Hubbuch, JT and Perry, JC. A naturalistic study of the chronic fatigue syndrome among women in primary care. General Hospital Psychiatry, 1998, 20, 5, 307-316.

This study explored subjects' perceptions of the variables that mediated the course of their illness and identified coping strategies in 15 women with CFS (CDC criteria '94) referred from the practice of a primary care physician.

Exploratory semistructured interviews were adapted from Kleinman's Illness Narratives. Measures included the Beck Depression Inventory, the Sickness Impact Profile, a modified Karnofsky scale (Bell), and the Defense Mechanism Rating Scale. Of the 15 women, 60% reported improvement and/or recovery at the time of the interview. Improvement was associated with social support and lower levels of depressive symptoms. Nearly three-quarters were working full or part-time. All had current or previous psychotherapy.

Health status was influenced by how subjects perceived their illness, their future, and the doctor's prognosis; and by early diagnosis, validation of the CFS, and intensive medical follow-up.

No evidence was found to support the view that CFS is an illness behaviour resulting from a need to opt out of work or family obligations (cf. Ware).

Obsessional and healthy neurotic defence levels predominated, which differs from historical comparison groups with dysthymia and panic disorder. Psychological adaptation to CFS is similar to adaptive coping in other chronic illnesses: subjective perceptions of health status can predict functional status. Physician validation is particularly important given the controversial status of CFS. Maintaining relationships with others, doctor, work, family, and group/spiritual activities reflected healthy coping strategies that promoted hope and attitudinal shifts. The finding of a mixture of neurotic and healthy defences and a low proportion of defences associated with personality disorders has not been previously reported in the CFS literature and warrants further investigation.

White, PD., Thomas, JM., Amess, J., Crawford, DH., Grover, SA., Kangro, HO and Clare, AW. Incidence, risk and prognosis of acute and chronic fatigue syndromes and psychiatric disorders after glandular fever. British Journal of Psychiatry, 1998, 173, 475-481.

A prospective cohort study of 250 primary care patients presenting with glandular fever and upper respiratory tract infections (URTI) were assessed using virological tests, a psychiatric interview (SADS), a fatigue questionnaire and the Hospital Anxiety and Depression Scale (HAD). Of the patients, 101 were confirmed as having glandular fever due to Epstein-Barr virus (EBV) and 83 as having non-EBV glandular fever. There were 54 people with URTIs. There were no differences between the three groups in terms of personality, stressful life events in the previous 6 months or their premorbid psychiatric history.

At 6 months, physical fatigue was reported by 40% in the EBV group, 29% in the non-EBV group compared with 15% in the URTI group. Excessive sleep was reported by 22% of those with EBV, 14% with non-EBV glandular fever and 2% with URTI. Of the 73 people with fatigue at 6 months, 38 (52%) met the Oxford criteria for CFS (although 5 also had CFS before onset), and EBV infection was found to be the greatest risk factor. Of the people with CFS, 42% had a psychiatric disorder, particularly depression. However, episodes tended to be of short duration. Of the 17 (23%) people who met the CDC '94 criteria for CFS, only 29% had a psychiatric disorder. There were no groups differences on the HAD at any time.

The incidence of CFS (Oxford criteria) was estimated to be 19% after EBV, 15% after non-EBV glandular fever and 2% after URTI. Using the CDC '94 criteria, the incidence was 9% in the post-infection groups and 0% after URTI.

The researchers conclude that glandular fever is a significant risk factor for both acute and chronic fatigue syndromes. Transient new major depressive disorders occur close to onset, but are not related to any particular infection, if they last more than a month.

THERAPEUTICS

See, DM., Cimoch, P., Chou, SW., Chang, J and Tilles, J. The in vitro immunomodulatory effects of glyconutrients on peripheral blood mononuclear cells of patients with chronic fatigue syndrome. Integrative Physiological and Behavioral Science, 1998, 33, 3, 280-287.

In humans, eight monosaccharides are required for the synthesis of glycoproteins. Dietary supplements that supply these crucial sugars are known as glyconutrients. A glyconutrient compound was added to PBMC isolated from 90 normal controls and 91 patients with CFS (CDC criteria '94). The in-vitro immunomodulatory effects were investigated.

Cell surface expression of the glycoproteins CD5, CD8, and CD11a were significantly lower in patients with CFS compared to normal controls. Addition of glyconutrient homogenate to PBMC from patients with CFS stimulated with phytohemagglutinin significantly increased the expression of each glycoprotein. Furthermore, natural killer (NK) cell function was reduced in CFS patients. The glyconutrient preparation significantly enhanced NK cell activity versus human herpes virus 6 (HHV-6)-infected H9 cells in an 8 h 51Cr release assay compared to placebo in blood from patients with CFS (p<.01). Finally, apoptosis was significantly higher in patients with CFS. The percentage of apoptotic cells was significantly decreased in PBMC from patients with CFS that had been incubated for 48 hours with glyconutrients. Thus, glyconutrients improved abnormal immune parameters in vitro in patients with CFS.

Commenting on the immunological findings, the authors note that "it is therefore apparent that CFS is a heterogeneous disorder with multiple subgroups... Some subgroups may benefit from glyconutritional supplementation... Immune dysfunction is present in some patients".

MISCELLANEOUS

Franklin, A. How I manage chronic fatigue syndrome. Archives of Disease in Childhood, 1998, 79, 4, 375-378.

An account of CFS in children by an experienced paediatrician.

Goudsmit, E. Treating chronic fatigue with exercise. British Medical Journal, 1998, 317, 599.

Letter challenging editorial by Sharpe and Wessely (ibid., 1998, 316, 796). Goudsmit notes that "CFS is now generally acknowledged to be a heterogeneous condition... what may suit one person, may be totally inappropriate for another. As research has shown, most patients with CFS remain ambulant, spend relatively few daytime hours resting, they are no more inactive than people with mild multiple sclerosis and tend to perform at or near their activity ceiling. What these patients need is not a strict programme where rest is pencilled in according to a predetermined plan, but a flexible approach which does not ignore current energy levels or make people feel guilty if they increase rest periods when they consider this to be right for them."

From a theoretical perspective, she comments that inactivity may well be an important factor in CFS, but that the authors did not provide a single reference to back their claim that many patients resort to "excessive rest". She asks if the theory of 'excessive inactivity' as a perpetuator of CFS is largely based on anecdotal reports and articles in magazines.

Goudsmit adds: "For many years, CFS specialists have argued that the emphasis on fatigue is misleading and that theories relating to this illness must not just be able to explain the lack of energy but also the fluctuations in the disorder and such symptoms as cognitive dysfunction, intolerance to alcohol and sensitivities to certain drugs". She asks if Sharpe and Wessely believe that these are also the result of 'excessive rest'?

"I have no doubt that graded exercise helps many people with CFS, notably those who are mildly affected (as shown by measures such as the Karnofsky scale), yet spend long periods in bed. However, the chronically fatigued do not constitute a homogenous population and the claim that "rest has no place" in their treatment is not only overly simplistic but inconsistent with the available evidence. The question is not whether patients should rest but when."

See also letter by Baschetti (p. 600) on the heterogeneity of CFS, the difference between conditions according to the definitions used and the possible role of adrenal insufficiency.

Michael in his letter (p. 600) comments that exercise can improve mood and sleep in fatigue syndromes.

Sharpe and Wessely reply that there may well be subgroups. However, they believe that level of disability does not influence response to rehabilitation. They add that a reduction in reported activity is required by the CDC 1994 definition and that research regarding cortisol is inconclusive. They reiterate that they are not aware of evidence that supports prolonged rest or that contraindicates appropriate increases in activity.

[Ed. note: Critics of the view that CFS is a single entity have not subdivided patients according to severity of disability but on the basis of onset, pattern of symptoms and relationship with psychiatric disorders. The CDC 1994 criteria specify there must be a substantial reduction in activities, but research has shown that this rarely amounts to total avoidance, as described by Sharpe and Wessely. There is no controversy about appropriate increases in activity; the question is whether patients should continue to exercise if unwell, as Wessely recommends, or whether they can stop or reduce activity at such times.]

Harlow, BL., Signorello, LB., Hall, JE., Dailey, C and Komaroff, AL. Reproductive correlates of chronic fatigue syndrome. American Journal of Medicine, 1998, 105, 3A, 94s-99s.

A study of 150 women with CFS (CDC criteria '88) using questionnaires revealed increased prevalence of gynaecological disorders compared with 149 non-gynaecological, non-CFS controls. Women with CFS reported more irregular cycles, sporadic bleeding between periods, polycystic ovarian syndrome, hirsutism and ovarian cysts. The lower prevalence of pre-menstrual symptoms prior to the CFS indicates they do not have a general tendency to report symptoms and illness (as in somatisation).

The researchers suggest that a history of anovulation or oligo-ovulation may be a risk factor for CFS.

Martin, WJ. Cellular sequences in stealth viruses. Pathobiology, 1998, 66, 2, 53-58.

Virological information on the stealth virus found in cultures from 4 patients with CFS.

Miller, BJ., Whiting, JL and Clouston, AD. Coincidental splenectomy in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 1998, 4, 1, 37-42.

This is a case report of a 27 year-old woman with CFS (CDC criteria '92). A splenectomy which was performed following a car crash revealed abnormalities suggestive of a chronic inflammatory process. The patient made a full recovery.

[Ed. note: One of our consultants considers this paper to be of interest because it describes the infiltration of CD45RO memory T cells into the spleen unconnected with the injury at the time of the car crash. He notes that one would not expect to find CD45RO cells congregating in the spleen unless they were signalled by the presence of some foreign protein such as a virus, infection etc.]

Teh, J., Scott, L., Dinan, E., Sohaib, A and Reznek, RH Adrenal size in chronic fatigue syndrome. Radiology, 1998, 209P (Suppl.), 411-412.

Abstract reporting a study of 8 patients with CFS (CDC criteria) who had a subnormal response on an ACTH stimulation test. A CT scan revealed that the right and left adrenal glands were reduced by 50% when compared with those of 55 healthy controls.

Watson, WS., McMillan, DC, Chaudhuri, A and Behan, PO. Increased resting energy expenditure in the chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 1998, 4, 4, 3-14.

It has been suggested that resting energy expenditure may be raised in CFS due to an upregulation of transmembrane ion transport. The researchers measured resting energy expenditure by indirect calorimetry in 11 women with chronic fatigue (own criteria) and in 11 healthy women. Total body potassium, by whole body counting, and total body water, extracellular water and intracellular water, by a bioelectrical impedance method, were also measured.

When individual resting energy expenditure was predicted on the basis of total body potassium values for the chronic fatigue group, 5 out of 11 of these subjects had resting energy expenditure above the upper limit of normal as defined by the control group data. This is consistent with the hypothesis that there is upregulation of the sodium-potassium pump in CFS.

There was no evidence that the results were due to lack of activity (this would also have affected total body water estimates).

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 and Mr. D. Axford.

The MCCSQ is funded by donations.

We dedicate this Capita Selecta to the memory of Mr. H. McNally.

Copyright EM. Goudsmit 1999. ©
Psychologist/Archivist, London.
All rights reserved. This article may not be reproduced without
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