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Volume 1, Number 3 |
1st September 1998 |
Swanink, CMA; Stolk-Engelaar, VMM; van der Meer, JWM; Vercoulen, JHMM; Bleijenberg, G; Fennis, JFM; Galama, JMD and Hoogkamp-Korstanje, JAA. Yersinia enterocolitica and the chronic fatigue syndrome. Journal of Infection, 1998, 36, 3, 269-272.
An immunoblot technique was used to detect antibodies to various Yersinia outer membrane proteins (YOPs) in serum samples from 88 patients with CFS (CDC criteria '94) and 77 healthy controls, matched for gender and age.
The prevalence of IgG and IgA antibodies to various YOPs did not differ between patients with CFS and healthy controls. Twenty-four patients (27%) and nineteen controls (25%) had IgG antibodies to one or more YOPs. Four patients and two controls had both serum IgG and IgA antibodies to at least two different YOPs, compatible with a recent or persistent infection. Although all patients with positive IgG and IgA reactions to two or more YOPs had symptoms that could point to persistent Yersinia infection, these symptoms were also frequently found in patients without antibodies to YOPs.
The researchers conclude that Yersinia enterocolitica is unlikely to play a major role in the aetiology of CFS.
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 significantly increased mean fluorescence intensity readings 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 general health perception and physical functioning scores. Increased spontaneous lymphocyte proliferation was associated with poor general health perception. PHA proliferative responses were lower in patients 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 costimulatory 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 aetiopathogenesis in the illness. The increased 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.
Hilgers, A., Frank, J and Bolte, P. Prolongation of central motor conduction time in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 1998, 4, 2, 23-32.
The central motor conduction time (CMCT) obtained by magnetic stimulation of the CNS was assessed in 181 patients with CFS (CDC criteria '94) and in 27 healthy controls. A cortical and a cervical stimulation was performed on each person under standardised conditions, and motor evoked potentials (MEP) either from the Musculus Abductor Digiti Minimi (M. ADM) or from the Musculus Abductor Pollicis Brevis (M. APB) were recorded.
For the CFS patients, a significant prolongation of the CMCT was observed compared to controls.
The findings in this study suggest a CNS dysfunction in CFS, possibly "a neurological disorder in the region between the motor cortex and the proximal spinal nerve in proximity to the intervertebral foramen".
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, LV., Burnett, F., Medbak, S and Dinan, TG. Naloxone-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome. Psychological Medicine, 1998, 28, 2, 285-293.
Opioidergic pathways have an inhibitory effect on the hypothalamic-pituitary-adrenal axis (HPA) in man. This is blocked by naloxone, leading to a rise in adrenocorticotropin (ACTH) and cortisol. Previous studies have suggested an impairment of pituitary-adrenal activation in CFS.
Thirteen patients with CFS (CDC criteria '94) were compared with thirteen healthy subjects. ACTH and cortisol responses were measured following the administration of .125 mg/kg naloxone.
Baseline ACTH and cortisol levels did not differ between the two groups. The release of ACTH (but not cortisol) was significantly blunted in the CFS subjects compared with controls.
"Naloxone mediated activation of the HPA is attenuated in CFS. Excessive opioid inhibition of the HPA is thus an unlikely explanation for the HPA dysregulation in this disorder". The possible explanations include an abnormality of the noradrenergic system.
Scott, LV., Medbak, S and Dinan, TG. The low dose ACTH test in chronic fatigue syndrome and in health. Clinical Endocrinology, 1998, 48, 6, 733-737.
The 1 µg ACTH test has been proposed to be more sensitive than the standard 250 µg ACTH test in the detection of subtle pituitary adrenal hypofunctioning.
In this study, 20 subjects with CFS (CDC criteria) were compared with 20 healthy volunteers. All participants underwent a 1 µg ACTH test beginning at 1400h. Plasma samples for cortisol estimation were drawn at 0, +30 and +40 min.
Baseline cortisol values did not differ between CFS patients and healthy subjects. The maximum change in cortisol values from base-line was significantly lower in the CFS patients than in the volunteers (p<0.05). Comparison of the +30 min cortisol values revealed no significant differences. Using an incremental cortisol value of >250 nmol/l as an arbitrary cutoff point, two (10%) of the healthy subjects and nine (45%) of the CFS subjects failed the test on this basis (p<0.05).
"This study provides further evidence for a subtle pituitary adrenal insufficiency in subjects with CFS compared to healthy volunteers. Disparities between our healthy volunteer data and those of other groups using the 1 µg ACTH test suggest that the test may not be as reliable as previously indicated".
Scott, LV; Medbak, S; Dinan, TG. Blunted adrenocorticotropin and cortisol responses to corticotropin-releasing hormone stimulation in chronic fatigue syndrome. Acta Psychiatrica Scandinavica, 1998, 97, 6, 450-457.
Blunted ACTH responses but normal cortisol responses to exogenous corticotropin-releasing hormone (CRH), the main regulator of the HPA axis, have been previously demonstrated in CFS patients, some of whom had a comorbid psychiatric disorder. The researchers wished to re-examine CRH activation of this axis in CFS patients free from concurrent psychiatric illness.
A sample of 14 patients with CFS (CDC criteria) were compared with 14 healthy volunteers. ACTH and cortisol responses were measured following the administration of 100 µg ovine CRH.
Basal ACTH and cortisol values did not differ between the two groups. However, the release of ACTH was significantly attenuated in the CFS group (p<.005), as was the release of cortisol (p<.05) compared to the controls.
The blunted response of ACTH to exogenous CRH stimulation may be due to an abnormality in CRH levels with a resultant alteration in pituitary CRH receptor sensitivity, or it may reflect a dysregulation of vasopressin or other factors involved in HPA regulation. A diminished output of neurotrophic ACTH, causing a reduced adrenocortical secretory reserve, inadequately compensated for by adrenoceptor upregulation, may explain the reduced cortisol production demonstrated in this study.
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.
Endicott, NA. Chronic fatigue syndrome: evidence of the premorbid anomalous patterns of brain organization. Psychosomatic Medicine, 1998, 60, 1, 132.
This abstract describes a study of 46 psychiatric patients with CFS, 92 healthy individuals and 46 psychiatric patients selected without regard to physical status. The results showed that psychiatric patients who later developed CFS had a significantly greater number of pre-CFS brain phenomena (e.g. learning problems, speech disorders, mixed or left handedness) than either of the comparison groups. This suggests that psychiatric patients who later develop CFS have a different pre-CFS pattern of brain organization than psychiatric patients who do not develop CFS.
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.
Morriss, RK and Weardon, AJ. Screening instruments for psychiatric morbidity in chronic fatigue syndrome. Journal of the Royal Society of Medicine, 1998, 91, 365-368.
In this study, 136 patients with CFS (Oxford criteria) were assessed using the Hospital Anxiety and Depression scale (HAD), the mental health scale of the MOS-SF and a psychiatric interview (CIS-R). The latter revealed that 10% met DSM-III-R criteria for major depression and 10% had anxiety disorders. A further 24% had dysthymia or another type of depressive disorder. Two per cent fulfilled criteria for somatisation disorder. It was found that the HAD scale at cut-off point 9/10 was a valid psychiatric screening instrument but that the MOS mental health scale was not.
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."
Essame, C., Phelan, S., Aggett, P and White, PD. Pilot study of a multidisciplinary inpatient rehabilitation of severely incapacitated patients with the chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 1998, 4, 2, 51-60.
This article focuses on the inpatient treatment (median 8 weeks) of 19 patients with CFS (Oxford criteria), all of whom were severely affected and 16 of whom had comorbid psychiatric disorders such as depression and somatization.
Treatment included graded activity, occupational and cognitive behaviour therapy, relaxation, supportive counselling, massage, dietary advice, high-dose antidepressants (for depression) and meeting with family and partners.
The median Karnofsky score on admission was 45, after treatment it was 60. More specifically, 89% improved after 8 weeks. The majority of these remained improved at the 1-year follow-up. None considered themselves cured, however.
[Ed. note: The vignettes strongly suggest that in these patients, comorbid psychiatric problems may have perpetuated their fatigue.]
Peterson, PK., Pheley, A., Schroeppel, J., Schenck, C.,Marshall, P., Kind, A., Haugland, JM., Lambrecht, LJ., Swan, S and Goldsmith, S. A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome. Archives of Internal Medicine, 1998, 158, 8, 908-914.
This article describes a placebo-controlled, double-blind, random allocation crossover trial of 6 weeks of fludrocortisone.
The sample comprised 25 moderate/severely affected patients with CFS (CDC criteria '88 and '94), recruited from a research and clinic registry. Five patients withdrew from the trial. All participants were scheduled to receive fludrocortisone acetate (0.1-0.2 mg) or a placebo for 6 weeks in each treatment.
The self-administered questionnaires which were completed at the beginning and end of each treatment arm, asked patients to rate the severity of their symptoms on a visual analogue scale. The MOS Short-Form, a mood questionnaire (PANAS), a reaction time test, and a treadmill exercise (walking) test were used to assess functional status. Blood pressure, heart rate, and plasma norepinephrine levels were obtained at baseline. Blood pressure and heart rate were recorded at the end of the exercise test and monitored at all subsequent visits.
At baseline, the participants reported symptom severity greater than 5 for most symptoms, and all had evidence of marked functional impairments. No significant improvement was observed in the severity of any symptom or in any test of function for the 20 participants who completed both arms of the trial. Blood pressure and heart rate readings were unaffected by treatment, and plasma norepinephrine levels did not differ from those of a healthy control group. The incidence of adverse experiences was similar in the fludrocortisone and placebo arms of the trial.
Conclusion: "Low-dose fludrocortisone does not provide sufficient benefit to be evident in a preliminary blinded trial of unselected patients with CFS".
Rowbottom, D., Keast, D., Pervan, Z., Goodman, C., Bhagat, C., Kakulas, B and Morton, A. The role of glutamine in the aetiology of the chronic fatigue syndrome: a prospective study. Journal of Chronic Fatigue Syndrome, 1998, 4, 2, 3-22.
This study assessed the therapeutic value of L-glutamine (2000 mg/day) versus placebo for 26 weeks in 16 patients with CFS (CDC criteria '88) and 16 healthy controls.
The plasma and muscle glutamine levels were found to be lower in the patients than the controls. These increased following supplementation but were not associated with improvements in symptoms.
Wearden, AJ., Morriss, RK., Mullis, R., Strickland, PL., Pearson, DJ., Appleby, L., Campbell, IT and Morriss, JA. Randomised, double-blind, placebo-controlled treatment trial of fluoxetine and graded exercise for chronic fatigue syndrome. British Journal of Psychiatry, 1998, 172, 485-490.
Patients with CFS (Oxford criteria), of
whom 46% had current psychiatric disorders, were randomly assigned to
four groups:
The number of drop outs from each group was: 1) 14; 2) 11; 3) 10 and 4) 5. The drop-outs tended to be more severely impaired (MOS-SF). Seventy-one per cent of the total sample completed the trial.
Graded exercise in the trial involved patients doing their preferred aerobic activity e.g. walking, jogging, swimming or cycling for 20 minutes, three times a week. The initial intensity was set at a level which utilised about 75% of the subject's tested functional maximum. Subjects monitored their programmes using a chart, heart-rate (measured pre and post exercise) and the perceived exertion scale (PES). Activities were increased when there was a consistent recorded reduction in heart rate (10 beats per minute) in post-exercise HR for one week and two points on the PES.
Measures included the fatigue scale (Chalder et al 1993), MOS-SF, HAD and a psychiatric interview (CIS-R). The physiological assessments included functional work capacity which was determined using a braked cycle ergometer and was calculated as the amount of oxygen consumed in the final minute of exercise per kilogram of body weight. All patients also kept special diaries which were discussed with the physiotherapists every four weeks.
Subjects were assessed at baseline and after 12 and 26 weeks. They had contact with the physiotherapist during weeks 0, 1, 2, 4, 8, 12, 20 and 26. Twenty-six per cent of subjects were members of self-help groups.
Graded exercise significantly improved functional work capacity but not fatigue. Fluoxetine was associated with lower depression scores at week 12 but had no effect on fatigue.
In those who completed the exercise treatment, there was a significant improvement on the MOS health perception scale at 26 weeks but not at 12 weeks. There was also a significant improvement in fatigue scores both at 12 and 26 weeks with a 12% reduction in patients with case level fatigue (score >4) by 26 weeks. Likewise, there was a 10% improvement in functional work capacity at 12 and 26 weeks. Exercise did not improve depression.
Of the 21 drop-outs assessed at 26 weeks, there was no worsening of fatigue, functional work capacity, MOS health perception or depression.
The researchers suggest that graded activity may provide patients with the reassurance that exercise at a controlled rate need not exacerbate fatigue.
With commentary by Deale, A., Chalder, T and Wessely, S (p. 491-492.) This notes the "modest" effects, which they attribute to behaviour change as a result of which there was a cognitive shift away from fear and avoidance. They add that 20 minutes may have been too much for some patients and that a more flexible programme could have produced a better outcome.
Chaudhuri, A., Behan, WMH and Behan, PO. Chronic fatigue syndrome. Proceedings of the Royal College of Physicians of Edinburgh, 1998, 28, 150-163.
Review of significant studies plus personal opinions based on the authors' clinical experience.
[Ed. note: the details about the research on post-exercise fatigue are misleading. There was a failure to recover in the normal manner, not a "rapid decline in quadriceps tension" after exercise.]
Komaroff AL and Buchwald DS. Chronic fatigue syndrome: an update. Annual Review of Medicine 1998, 49, 1-13.
Concise review.
[Ed. note: the evaluation of CBT programmes ignores the criticism of this approach as a universal treatment (e.g. Jason et al).]
De Lorenzo, F., Hargreaves, J and Kakkar, VV. Phosphate diabetes in patients with chronic fatigue syndrome. Postgraduate Medical Journal, 1998, 74, 870, 229-232.
Phosphate depletion is associated with neuromuscular dysfunction due to changes in mitochondrial respiration that result in a defect of intracellular oxidative metabolism. Phosphate diabetes (PD) causes phosphate depletion due to abnormal renal re-absorption of phosphate by the proximal renal tubule. Most of the symptoms described by patients with PD such as myalgia, fatigue and mild depression, are also common in CFS but this differential diagnosis has not been considered.
The researchers investigated the possible association between CFS and PD in 87 patients with CFS (CDC criteria '88). Control subjects were 37 volunteers who explicitly denied fatigue and chronic illness on a screening questionnaire. They provided urine and serum samples for the study. Re-absorption of phosphate by the proximal renal tubule, phosphate clearance and renal threshold phosphate concentration (TmPO4/GFR) were the main outcome measures.
The results indicated that 9 of the CFS patients fulfilled the diagnostic criteria for PD (phosphate clearance >15 ml/min and/or the phosphate tubular re-absorption (PTR) <85% plus TmPO4/GFR) <0.8 mmol/l.
The researchers suggest that PD should be considered as a differential diagnosis and that future research might investigate the possible benefits of vitamin D and oral phosphate supplements.
Korszun, A., Papadopoulos, E., Lundeen, L., Engleberg, C., Demitrack, M., Haus, E and Crofford, L. Melatonin secretion in temporomandibular disorders, fibromyalgia and chronic fatigue syndrome. Journal of Dental Research, 1998, 77, 772: 1128.
Abstract reporting the study of 17 premenopausal women with fibromyalgia and/or CFS, 8 with and 9 without temporomandibular disorder and 17 age and menstrual cycle phase matched controls. Blood was collected every 10 minutes over 24 hours. Melatonin levels were determined every hour.
Nocturnal melatonin levels were significantly higher in all patients compared to controls (p<.002). There were no significant differences in mean 24 hour cortisol levels between the groups.
Since melatonin concentrations are increased in stress-related conditions, the results "may represent a marker of increased hypothalamic susceptibility to pathological sequelae of stress".
Loge, JH., Ekeberg, O and Kaasa, S. Fatigue in the general Norwegian population: normative data and associations. Journal of Psychosomatic Research, 1998, 45, 1, 53-65.
A mailed questionnaire was sent to a random sample of Norwegians. This included items from the Chalder fatigue scale. The information used in the analysis (n=2323) revealed that 22% of patients reported substantial fatigue and that 11% fulfilled the criteria for 'case-ness' (score >4 and duration of 6 months or more). There were more cases among women than men, and more among those with health problems.
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.
Moorkens, G., Keenoy, BMY., Vertommen, J., Meludu, S., Noe, M and De Leeuw, I. Magnesium deficit in a sample of the Belgian population presenting with chronic fatigue. Magnesium Research, 1997, 10, 4, 329-337.
This study involved 97 patients with chronic fatigue lasting at least one month. Fifty-four per cent presented with symptoms compatible with CFS; 52% fulfilled the criteria for fibromyalgia. Other diagnoses included spasmophilia.
Forty-seven per cent of the sample retained 20% or more of the magnesium infused during the parental loading test and were classed as Mg deficient. After supplementation in 24 patients, the loading test showed a significant decrease in Mg retention (i.e. a sign of improvement in the body stores of Mg). The mean values of Mg measured in other ways e.g. red blood cell Mg, serum Mg and in urine, showed no difference between patients with and without Mg deficiency as defined using the loading test. There was no association between Mg deficiency and CFS. Mg status was related to dietary intake of fibre and protein.
Ottenweller, JE., Natelson, BH., Gause, WC., Carroll, KK., Beldowicz, D., Zhou, XD and LaManca, JJ. Mouse running activity is lowered by Brucella abortus treatment: a potential model to study chronic fatigue. Physiology & Behavior, 1998, 63, 5, 795-801.
Chao et al and others have reported decreases in mouse running activity following infection and have suggested this may provide an animal model for studying chronic fatigue.
Following 2 weeks of acclimatisation to running wheels with food and water available ad lib, Female BALB/c mice received 0.2-mL tail vein injections of killed Brucella abortus (BA) or saline vehicle. Subsequently the effects on voluntary running and grooming behaviour were determined.
Injection of BA caused an immediate large decrease in running and a lack of grooming. Vehicle injections produced no changes in behaviour. The mice ran as fast as controls after about 5 days, but not for as long. After the first few days of reduced running behaviour, total levels of running and grooming (i.e. including duration) slowly returned back to normal over the next 2-4 weeks, with substantial individual differences in the rate of recovery (range 13-41 days, median: 23 days).
After 31 days, the mice who were still showing reduced activity were sacrificed, and found to have lower levels of IL-2 and IL-4 splenic lymphocyte mRNA and higher levels of IL-10.
The researchers conclude that: "the model may be a good one for studying the biologic underpinnings of chronic fatigue."
Peroutka, SJ. Chronic fatigue disorders: an inappropriate response to arginine vasopressin? Medical Hypotheses, 1998, 50, 6, 521-523.
The author hypothesises that a clinical overlap exists between chronic fatigue disorders and the syndrome of serum inappropriate anti-diuretic hormone (SIADH). Both are characterised by lethargy and mental confusion and both can be induced or exacerbated by viral illnesses, physical exertion, emotional stress and/or hypotension. Both can be treated with salt loading and glucocorticoids. Therefore, altered water metabolism resulting from inappropriate release and/or response to arginine vasopressin (AVP) is proposed as a pathophysiological basis of certain chronic fatigue disorders. Moreover, these data suggest that salt loading and/or direct inhibition of AVP may be an effective therapeutic approach in individuals with chronic fatigue disorders.
Nisenbaum, R., Reyes, M., Mawle, AC and Reeves, WC. Factor analysis of unexplained severe fatigue and interrelated symptoms. Overlap with criteria for chronic fatigue syndrome. American Journal of Epidemiology, 1998, 148, 1, 72-77.
Between June and December of 1994, a cross-sectional, random digit dialling telephone survey was conducted among residents of San Francisco, California. All subjects who reported having severe fatigue lasting for >1 month and a random sample of nonfatigued subjects were asked to participate in a detailed telephone interview. Data from 1,510 individuals aged 18-60 years who did not have medical or psychiatric conditions that could explain their severe fatigue were analysed. They were asked about the presence of 30 symptoms during the past 4 weeks and the study compared the results among patients with fatigue >1 month (n=177), > 6 mths (n=255) and persons without fatigue (n=1078).
Common factor analysis identified three correlated factors (defined as "fatigue-mood-cognition" symptoms, "flu-type" symptoms, and "visual impairment") that were associated with fatigue lasting for > 6 months. No factor explained the correlations among fatigue lasting for 1-5 months and other symptoms. The combination of fatigue of > 6 months' duration and selected symptoms overlaps with published criteria used to define cases of CFS.
Nouri, S., Zumo, L and Kaufmann, H. Autonomic cardiovascular reflexes in chronic fatigue syndrome. Neurology, 1998, 50, 4 Suppl, A360-A361.
This abstract describes a study of 25 patients with CFS (CDC criteria) and 50 healthy controls. Tests included heart rate, blood pressure, and a 60 head-up tilt (HUT) for 40 minutes or until pre-syncope/syncope occurred.
HUT elicited neurally mediated syncope in 6% of the controls and 16% of the CFS patients (p<.05). The maximum increase in heart rate during HUT was significantly higher in CFS patients (p<.05). These CFS patients had preserved autonomic cardiovascular reflexes but exaggerated orthostatic tachycardia. The reasons for the findings remain unclear.
Russo, J., Katon, W., Clark, M., Kith, P, Sintay, M and Buchwald, D. Longitudinal changes associated with improvement in chronic fatigue syndrome. Journal of Psychosomatic Research, 1998, 45, 1, 67-76.
This report describes 98 patients with fatigue who were followed for an average of 2.5 years. Factors which predicted a good outcome (improved functioning and return to work) were not meeting the criteria for CFS, or only at the first assessment, and loss of physical examination signs. Associated with poor outcome were the presence of physical signs and psychological distress.
At follow-up, 26% were 'worse', 2.6% were fully recovered, and 41% reported a moderate to complete recovery. Nearly one-third had returned to work. Twenty per cent had a psychiatric diagnosis (DIS) at Time 1 and 2, and 15% met the criteria for CFS (CDC '88) at Time 1 and 2.
Speight, ANP. Increased illness experience preceding chronic fatigue syndrome. Journal of the Royal College of Physicians of London, 1998, 32, 3, 274.
Letter criticising the interpretation of the findings by Hall et al (ibid., 1998, 44-48). The author notes that the increased number of symptoms prior to diagnosis of CFS could have been early but unrecognised signs of the illness, rather than 'abnormal illness behaviour'. He adds that in some patients, there was no excess consultation rate prior to diagnosis, and thus no evidence of abnormal illness behaviour. Thirdly, since the researchers had not examined the patients but based their work on records, it is not valid to conclude that the cause of CFS is psychological. See also a less critical letter by Cohen, SI.
Stores, G., Fry, A and Crawford, C. Sleep abnormalities demonstrated by home polysomnography in teenagers with chronic fatigue syndrome. Journal of Psychosomatic Research, 1998, 45, 1, 85-91.
Overnight polysomnography at home was performed on 18 children with CFS (Oxford criteria, fatigue of two months or longer) and 18 matched controls (11-17 years age group).
There were a number of differences between the groups. For instance, the CFS patients had more disruptions during sleep and a reduction in NREM sleep stage 2. The researchers note that the disrupted sleep and longer awakenings could contribute to daytime sleepiness.
Streeten, DHP and Anderson, GH. The role of delayed orthostatic hypotension in the pathogenesis of chronic fatigue. Clinical Autonomic Research, 1998, 8, 2, 119-124.
The researchers determined the prevalence of fatigue, volunteered in response to a non-specific pre-examination questionnaire used in 431 patients, each subsequently diagnosed as having one of eight neurological or endocrine disorders.
The results showed that fatigue is a very common symptom in patients with delayed orthostatic hypotension (n=21), as well as both primary (n=30) and secondary (n=106) hypocortisolism: 70-83% in all groups. In contrast, fatigue was an uncommon complaint in patients with multiple system atrophy (MSA) (n=30), pituitary disorders without hypocortisolism (n=106) or idiopathic hirsutism (n=96): 7-33% in all groups, and was intermediate in prevalence in patients with acute hyperadrenergic orthostatic hypotension (n=32): 41%.
There was a high prevalence (93%) of orthostatic hypotension in patients with CFS (CDC criteria '94, n=45).
It is concluded that fatigue commonly results from delayed orthostatic hypotension and all forms of hypocortisolism but is less common in patients with acute orthostatic hypotension, both idiopathic and due to MSA, which more commonly present with light-headedness or syncope.
Bennett, BK., Hickie, IB., Volmer Conna, US., Quigley, B., Brennan, CM., Wakefield, D., Douglas, MP., Hansen, GR., Tahmindjis, AJ and Lloyd, AR. The relationship between fatigue, psychological and immunological variables in acute infectious illness. Australian and New Zealand Journal of Psychiatry, 1998, 32, 2, 180-186.
Thirty patients with acute infections were followed for 4 weeks.
At baseline, 69% reported psychological distress on the GHQ-12; at 4 weeks, the number of cases was 27%. All reported fatigue when first seen and of these, 63% remained fatigued at follow-up. A reduction in fatigue correlated with an improvement in delayed-type hypersensitivity responses, a measure of cell-mediated immune function, and GHQ scores. At 4 weeks, the fatigue appeared to have "an immunological basis".
Bennett, RM., Clark, SC and Walczyk, J. A randomized, double-blind, placebo-controlled study of growth hormone in the treatment of fibromyalgia. American Journal of Medicine, 1998, 104, 227-231.
A sample of 51 women with fibromyalgia and low levels of insulin-like growth factor 1 was split into two groups. One was given injections of growth hormone (up to 250 ng/mL, the other a placebo. The treatment group (completed n=22, 11 of whom fulfilled criteria for CFS), showed a significant improvement over the placebo group (n=23) at 9 months on measures of symptoms and disability. However, there was often a delay of 6 months before improvements were noted. After discontinuing treatment, there was a worsening of symptoms. Adverse reactions included carpal tunnel symptoms.
Ford, H., Trigwell, P and Johnson, M. The nature of fatigue in multiple sclerosis. Journal of Psychosomatic Research, 1998, 45, 1, 33-38.
A study of 78 patients with MS revealed that 85% had scores on the Chalder et al Fatigue Scale indicating significant fatigue. Both mental and total fatigue scores were significantly correlated to the score on the anxiety and depression subscales of the HAD. There was also a trend towards significant correlations between physical fatigue scores and anxiety and depression. Of the sample, 36.8% scored above the cut-off point for clinically significant anxiety and 19.1% above the cut-off point for depression.
Copyright EM. Goudsmit 1998.
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