NEUROLOGY

Lange, G., Holodny, AI., DeLuca, J., Lee, H-J., Yan, XH., Steffener J and Natelson BH. Quantitative assessment of cerebral ventricular volumes in chronic fatigue syndrome. Applied Neuropsychology, 2001, 8, 1, 23-30.

Previous qualitative volumetric assessment of lateral ventricular enlargement in CFS has provided evidence for subtle structural changes in the brains of some individuals with CFS. The aim of this pilot study was to determine whether a more sensitive quantitative assessment of the lateral ventricular system would support the previous qualitative findings.

In this study, we compared the total lateral ventricular volume, as well as the right and left hemisphere subcomponents in 28 patients with CFS (CDC criteria '94 plus additional criteria) and 15 controls. 

Ventricular volumes in the CFS group were larger than in control groups, a difference that approached statistical significance. For example, the CFS patients showed a larger mean volume of the lateral ventricular system compared to controls (p<.057). The volumetric measurements were not related to psychiatric illness (documented in some of the patients), or perceived severity. Group differences in ventricular asymmetry were not observed. 

The results of this study provide further evidence of subtle pathophysiological changes in the brains of some patients with CFS.

• [Ed. note: Ventricular enlargement is a non-specific finding but has been linked to white matter loss, metabolic abnormalities and traumatic brain injury.]

Lewis, DH., Mayberg, HS., Fischer, ME., Goldberg, J., Ashton, S, Graham, MM and Buchwald, D.  Monozygotic twins discordant for chronic fatigue syndrome: regional cerebral blood flow SPECT. Radiology, 2001, 219, 3, 766-773.

The aim of this study was to evaluate the relationship between regional cerebral blood flow (rCBF) and CFS in monozygotic twins discordant for CFS. The authors conducted a co-twin control study of 22 twins in which one met the CDC '94 criteria for CFS and the other was healthy. Twins underwent a structured psychiatric interview and resting technetium 99m-hexamethyl-propyleneamine oxime single photon emission computed tomography of the brain. They also rated their mental status before the procedure. Scans were interpreted independently by two physicians blinded to illness status and then at a blinded consensus reading. Imaging fusion software with automated three-dimensional matching of rCBF images was used to coregister and quantify results.

Outcomes were the number and distribution of abnormalities at both reader consensus and automated quantification. Mean rCBF levels were compared by using random effects regression models to account for the effects of twin matching and potential confounding factors.

The twins with and those without CFS were similar in mean number of visually detected abnormalities and in mean differences quantified by using image registration software. These results were unaltered with adjustments for fitness level, depression, and mood before imaging.

The study results did not provide evidence of a distinctive pattern of resting rCBF abnormalities associated with CFS. 

• [Ed. note: There are no data for perfusion in the brainstem cf Costa et al. Studies which reported hypoperfusion used stricter criteria.]

Paul, LM., Wood, L and Maclaren, W. The effect of exercise on gait and balance in patients with chronic fatigue syndrome. Gait and Posture, 2001, 14, 1, 19-27.

This study investigated anecdotal reports of gait and balance abnormalities in subjects with CFS by examining the effects of a light exercise test on postural sway and various gait parameters. Tests were performed on 11 CFS patients (London and CDC criteria '94) and 11 age- and sex-matched sedentary controls.

The results demonstrated that postural sway was not significantly different in both groups before or after the exercise test.

There were, however, significant differences in gait parameters between the two groups confirming anecdotal evidence, but these differences were not exacerbated by the exercise test. Heart rate responses demonstrated that both groups were exercising at similar loads, although this was perceived to be higher by the CFS group.

• [Ed. note: The exercise was light and lasted just 15 minutes. There is no information as to whether these patients had symptoms of disequilibrium as part of their illness.]

PHYSIOLOGY, NEUROPHYSIOLOGY AND NEUROENDOCRINOLOGY

Hamilos, DL., Nutter, D., Gershtenson, J., Ikle, D., Hamilos, SS., Redmond, DP., Di Clementi, JD., Schmaling, KB and Jones JF. Circadian rhythm of core body temperature in subjects with chronic fatigue syndrome. Clinical Physiology, 2001, 21, 2, 184-195.

Certain symptoms of CFS, namely fatigue, neurocognitive symptoms and sleep disturbance, are similar to those of acute jet lag and shift work syndromes thus raising the possibility that CFS might be a condition associated with disturbances in endogenous circadian rhythms. This hypothesis was tested by examining the circadian rhythm of core body temperature (CBT) in CFS and control subjects. Continuous recordings of CBT were obtained every 5 min over 48 hours in a group of 10 subjects with CFS (CDC definition) and 10 normal control subjects. Subjects in the two groups were age, sex and weight‑matched and were known to have normal basal metabolic rates and thyroid function.

CBT recordings were performed under ambulatory conditions in a clinical research centre with the use of an ingestible radio frequency transmitter pill and a belt-worn receiver-logger. 

By cosinor analysis, the only significant difference between CFS and control groups was in the phase angle of the third harmonic (p=0.02). 

..."Measured under ambulatory conditions, the circadian rhythm of CBT in CFS is nearly indistinguishable from that of normal control subjects although there was a tendency for greater variability in the rhythm. Hence, it is unlikely that the symptoms of CFS are because of disturbance in the circadian rhythm of CBT."

Naschitz, JE.,  Rozenbaum, M,  Rosner, I., Sabo, E., Priselac, RM., Shaviv, N., Ahdoot, A., Ahdoot, M., Gaitini, L., Eldar, S and Yeshurun, D. Cardiovascular response to upright tilt in fibromyalgia differs from that in chronic fatigue syndrome. Journal of Rheumatology, 2001, 28, 1356-1360.  

The aim of this study was to compare the cardiovascular response during postural challenge of patients with fibromyalgia (FM) to those with CFS. Age and sex matched patients were studied, 38 with FM, 30 with CFS, and 37 healthy subjects. Blood pressure (BP) and heart rate (HR) were recorded during 10 minutes of recumbence and 30 minutes of head-up tilt. Differences between successive BP values and the last recumbent BP, their average, and standard deviation were calculated. Time curves of BP differences were analyzed by computer and their outline ratios (OR) and fractal dimensions (FD) were measured. HR differences were determined similarly. Based on the latter measurements, each subject's discriminant score (DS) was computed. 

For patients and controls average DS values were: FM: -3.68, CFS: 3.72, and healthy controls: -4.62. DS values differed significantly between FM and CFS (p<0.0001). Subgroups of FM patients with and without fatigue had comparable DS values. 

The DS confers numerical expression to the cardiovascular response during postural challenge. DS values in FM were significantly different from DS in CFS, suggesting that homeostatic responses in FM and CFS are dissimilar. This observation challenges the hypothesis that FM and CFS share a common derangement of the stress-response system. 

Tomoda, A., Jhodoi and Miike, T. Chronic fatigue syndrome and abnormal biological rhythms in school children. Journal of Chronic Fatigue Syndrome, 2001, 8, 2, 29-37. 

Study of 41 adolescents with CFS (CDC criteria '88) revealed abnormalities in circadian core body temperature rhythms and circadian cortisol rhythm compared to controls. The desynchronization of these rhythms is a possible therapeutic target. 

Vassallo, CM., Feldman, E., Peto, T., Castell, L., Sharpley AL and Cowen, PJ. Decreased tryptophan availability but normal post-synaptic 5‑HT_2c receptor sensitivity in chronic fatigue syndrome. Psychological Medicine, 2001, 31, 4, 585-591.

CFS has been associated with increased prolactin (PRL) responses to the serotonin (5-HT) releasing agent fenfluramine. It is not known whether this abnormality is due to increased 5-HT release or heightened sensitivity of post-synaptic 5-HT receptors.

The increase in plasma PRL produced by the directly acting 5-HT receptor agonist, m-chlorophenylpiperazine (mCPP), was measured in 20 patients with CFS (all except one fulfilled Oxford and CDC criteria for CFS, all met criteria for neurasthenia)^* and 21 healthy controls. The ability of mCPP to lower slow wave sleep (SWS) in the sleep polysomnogram of both subject groups (n=11 in patients and controls) was also compared. Finally, the researchers measured plasma amino-acid levels to determine whether tryptophan availability differed between CFS subjects and controls.

mCPP elevated plasma PRL was similar in patients with CFS and controls. Likewise, the decrease in SWS produced by mCPP did not differ between the two subject groups. Plasma-free tryptophan was significantly decreased in CFS (p=.033).

The sensitivity of post-synaptic 5-HT_2c receptors is not increased in patients with 'CFS'. This suggests that the increased PRL response to fenfluramine in CFS is due to elevated activity of presynaptic 5-HT neurones. This change is unlikely to be due to increased peripheral availability of tryptophan.

• * [Ed. note: ME/PVFS is an exclusion under the ICD criteria for neurasthenia.]

GENETICS

Underhill, JA., Mahalingam, M., Peakman, M and Wessely, S. Lack of association between HLA genotype and chronic fatigue syndrome. European Journal of Immunogenetics, 2001, 28, 3, 425-428.

Although the aetiology of CFS is controversial, evidence that infective agents including viruses may have a role in the development of the condition has led to studies seeking an association with the immunomodulatory HLA genes. In the present study, the researchers sought to extend previous work using modern HLA genotyping techniques.

Fifty-eight patients were phenotyped for HLA A and B by microcytotoxicity and genotyped for HLA DRB, DQB and DPB by PCR oligoprobing, and the frequencies of antigens so assigned were compared with those from a control group of 134. 

No significant differences in HLA frequencies were found between patient and control groups. Thus, this study does not confirm previous findings of an HLA association with CFS, suggesting that neither presentation of viral antigen by HLA class I nor antigen processing genes in the HLA region is a major contributory factor in the development of the disease.

PSYCHOLOGY AND PSYCHIATRY

Claypoole, K., Mahurin, R., Fischer, ME., Goldberg, J., Schmaling, KB., Schoene, RB., Ashton, S and Buchwald D. Cognitive compromise following exercise in monozygotic twins discordant for chronic fatigue syndrome: fact or artifact?  Applied Neuropsychology, 2001, 8, 1, 31-40.

This study examined the effects of exhaustive exercise on cognitive functioning among 21 monozygotic twin pairs discordant for CFS (CDC criteria '94). 

Participants pedalled a cycle ergometer to exhaustion; maximum oxygen output capacity (VO2max) as well as perceived exertion were recorded. Neuropsychological tests of brief attention and concentration, speed of visual motor information processing, verbal learning and recognition memory, and word and category fluency were administered with alternate forms to participants pre- and post-exercise.

The pre-exercise neuropsychological test performance of CFS twins tended to be slightly below that of the healthy twin controls on all measures. However, twins with CFS did not demonstrate differential decrements in neuropsychological functioning after exercise relative to their healthy co‑twins. Because exercise does not appear to diminish cognitive function, rehabilitative treatment approaches incorporating exercise are not contraindicated in CFS.

Daly, E., Komaroff, AL., Bloomingdale, K., Wilson, S and Albert MS. Neuropsychological function in patients with chronic fatigue syndrome, multiple sclerosis, and depression. Applied Neuropsychology, 2001, 8, 1, 12-22.

Patients with CFS, multiple sclerosis (MS), and major depression were compared with controls and with each other on a neuropsychological battery that included standard neuropsychological tests and a computerized set of tasks that spanned the same areas of ability.

A total of 101 participants were examined, including 29 participants with CFS (CDC criteria '92), 24 with MS, 23 with major depressive disorder, and 25 healthy controls. 

There were significant differences among the groups in 3 out of 5 cognitive domains: memory, language, and spatial ability. Assessment of psychiatric symptoms indicated that all 3 patient groups had a higher prevalence of depression than the controls. A total measure of psychiatric symptomatology also differentiated the patients from the controls. After covarying the cognitive test scores by a measure of depression, the patient groups continued to differ from controls primarily in the area of memory.

The findings support the view that the cognitive deficits found in CFS cannot be attributed solely to the presence of depressive symptomatology in the patients.

Deale, A and Wessely, S. Patients' perceptions of medical care in chronic fatigue syndrome. Social Science and Medicine, 2001, 52, 12, 1859-1864.

This study investigated perceptions of medical care among patients with CFS referred to a specialist clinic. Sixty-eight patients with CFS (Oxford criteria) completed a questionnaire survey on their overall satisfaction with medical care received since the onset of their illness, and their views on specific aspects of care. Of these, 34% had a co-morbid psychiatric disorder. A quarter were members of a patient association. 

Two-thirds of patients, more women than men, were dissatisfied with the quality of medical care received. Over 80% had been prescribed medication, most commonly antidepressants. Dissatisfied patients were significantly more likely to describe delay, dispute or confusion over diagnosis; to have received and rejected a psychiatric diagnosis; to perceive doctors as dismissive, sceptical or not knowledgeable about CFS and to feel that the advice given was inadequate or conflicting.

Satisfied patients were significantly more likely to perceive doctors as caring, supportive and interested in their illness; to state that they did not expect their doctors to cure CFS and to perceive their GP or hospital doctor as the source of greatest help during their illness. Many patients were critical of the paucity of treatment, but this was not associated with overall satisfaction.

The findings suggest that medical care was evaluated less on the ability of doctors to treat CFS, and more on their interpersonal and informational skills. Dissatisfaction with these factors is likely to impede the development of a therapeutic doctor-patient alliance, which is central to the effective management of CFS. The findings suggest a need for better communication and better education of doctors in the diagnosis and management of CFS.

Jason, LA., Taylor, RR., Kennedy, CL., Song, S., Johnson, D and Torres, S. Chronic fatigue syndrome: comorbidity with fibromyalgia and psychiatric illness. Medicine & Psychiatry, 2001, 4, 29-34. 

Pursuit of explanation for prior inconsistent physiological and  psychological findings among individuals with CFS has led researchers to examine heterogeneity among patient samples that may result from the presence of comorbid illnesses.  Most studies of CFS have been based on patients recruited from primary or tertiary care settings. Patients from such settings might not be typical of patients in the general population. 

The present study was intended to examine differences between individuals with CFS with respect to comorbid FM and psychiatric illness. The data came from the community survey (described elsewhere). 

The individuals with CFS and comorbid FM demonstrated more symptom severity and functional impairment than individuals with CFS alone. Individuals with CFS and current or lifetime psychiatric diagnoses demonstrated greater fatigue and functional limitations. 

Discrepancies among CFS research findings may be, in part, attributed to comorbidity with other medical and psychiatric illness. 

Patarca-Montero, R., Antoni, M., Fletcher, MA and Klimas NG. Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors. Applied Neuropsy-chology, 2001, 8, 1, 51-64.

The literature is reviewed and data are presented that relate to a model we have developed to account for the perpetuation of the perplexing disorder currently termed CFS.

In patients with CFS there is chronic lymphocyte overactivation with cytokine abnormalities that include perturbations in plasma levels of proinflammatory cytokines and a decrease in the ratio of Type 1 to Type 2 cytokines produced by lymphocytes in vitro following mitogen stimulation.

The initiation of the syndrome is frequently sudden and often follows an acute viral illness. Our model for the subsequent chronicity of this disorder holds that the interaction of psychological factors (distress associated with either CFS-related symptoms or other stressful life events) and the immunologic dysfunction contribute to (a) CFS-related physical symptoms (e.g., perception of fatigue and cognitive difficulties, fever, muscle and joint pain) and increases in illness burden and (b) impaired immune surveillance associated with cytotoxic lymphocytes with resulting activation of latent herpes viruses.

Ross, S., Fantie, B., Straus, SF and Grafman J. Divided attention deficits in patients with chronic fatigue syndrome. Applied Neuropsychology, 2001, 8, 1, 4-11.

CFS patients and controls were compared on a variety of mood state, personality, and neuropsychological measures, including memory, word finding, and attentional tasks that required participants to focus, sustain, or divide their attention, or to perform a combination of these functions.

CFS patients demonstrated a selective deficit on 3 measures of divided attention. Their performance on the other neuropsychological tests of intelligence, fluency, and memory was no different than that of normal controls despite their reports of generally diminished cognitive capacity.

There was an inverse relation between CFS patient fatigue severity and performance on 1 of the divided attention measures.

Given these findings, it is probable that CFS patients will report more cognitive difficulties in real-life situations that cause them to divide their effort or rapidly reallocate cognitive resources between 2 response channels (vision and audition).

Taylor, RR, Jason LA, Kennedy, CL and Friedberg, F. Effect of physician-recommended treatment on mental health practitioners' attributions for chronic fatigue syndrome. Rehabilitation Psychology, 2001, 46, 2, 165-177.

The aim was to evaluate whether differing treatment recommendations for CFS by physicians influence attributions about CFS among mental health practitioners.

Ninety-three mental health practitioners (social work interns, clinical psychology trainees, licensed clinical social workers, and licensed clinical psychologists) were randomly assigned to 1 of 3 conditions. All groups read the same case study of a person diagnosed with CFS, with the only difference between groups being the type of treatment recommended by a physician. The treatment conditions included a drug trial (Ampligen, n=29) or 1 of 2 differing psychotherapy approaches, cognitive‑behaviour therapy (CBT) with graded activity (n=32) or cognitive coping skills therapy (n=32).

Outcome measures included attributions regarding the illness, including impressions about its aetiology, diagnostic accuracy, severity, prognosis, and the expected outcome of the proposed treatment; familiarity with CFS.

Participants in the 3 groups did not differ with respect to their prior familiarity with CFS and the majority regarded CFS as a medical disorder. Participants who read the case study proposing treatment with Ampligen were more likely to report that the patient was correctly diagnosed and more likely to perceive the patient as disabled than those whose case study described CBT therapy with graded activity as the treatment.

Results of this investigation support the hypothesis that physician recommendations for CFS treatment can influence subsequent attributions about a patient's illness among mental health practitioners. This study is relevant in terms of the stigmatisation of CFS where people are deemed to possess an attribute which conveys a devalued social identity. 

• [Ed. note: Most articles on CBT tend to associate CFS with negative attributes which are linked with the perpetuation of the illness. The total lack of positive attributes reinforces a one dimensional stereotype and thus contributes to the stigmatisation of CFS. This is known to many of the authors of those articles.]

Taylor, RR., Taylor, LA and Schoeny, ME. Evaluating latent variable models of functional somatic distress in a community-based sample. Journal of Mental Health, 2001, 10, 335-349. 

This study evaluated the diagnostic validity of conditions that have been labelled, functional somatic syndromes. In an effort to replicate prior work in this area, latent variable models of functional somatic distress were estimated from the responses of 213 community members to a medical questionnaire. Medical questionnaire items that closely conformed to formal diagnostic criteria for the conditions were used in model estimation. 

Results of confirmatory factor analysis supported diagnostic distinctions between five syndromes (FM, CFS, somatic depression, somatic anxiety, and irritable bowel syndrome). Discrete diagnostic categories of FM and CFS were then tested using logistic regression analysis, in which the outcome involved independent diagnosis of these conditions based upon physician evaluation. 

Evidence for the existence of discrete diagnoses of FM and CFS was particularly strong, since these diagnoses were cross-validated using findings from physician evaluation tailored to diagnose these conditions. 

"In contrast to prior reports (Deary 1999, Robbins et al 1997), findings from the present study did not provide strong support for the existence of an overarching entity of functional somatic distress" ... to conclude that it is plausible that syndromes such as FM and CFS may be reasonably explained in terms of a larger construct of generalized somatic distress that also includes somatic depression and somatic anxiety "would be erroneous, given  findings from the present study."

Tiersky, LA., DeLuca, J., Hill, N., Dhar, SK., Johnson, SK., Lange, G., Rappolt, G and Natelson BH. Longitudinal assessment of neuropsychological functioning, psychiatric status, functional disability and employment status in chronic fatigue syndrome. Applied Neuropsychology, 2001, 8, 1, 41-50.

The longitudinal course of subjective and objective neuropsychological functioning, psychological functioning, disability level, and employment status in CFS was examined. The relations among several key outcomes at follow-up, as well as the baseline characteristics that predict change (e.g., improvement), were also evaluated.

The study sample consisted of 35 individuals with CFS (CDC criteria '88 and '94) at intake. Participants were evaluated a mean of 41.9 months following their initial visit (range = 24-63 months).

Results indicated that objective and subjective attention abilities, mood, level of fatigue, and disability improve over time. Moreover, improvements in these areas were found to be interrelated at follow-up. Finally, psychiatric status, age, and between-test duration were significant predictors of outcome.

Overall, the prognosis for CFS appears to be poor, as the majority of participants remained functionally impaired over time and were unemployed at follow-up, despite the noted improvements.

EPIDEMIOLOGY

Hamilton, WT., Hall, GH and Round, AP.  Frequency of attendance in general practice and symptoms before development of chronic fatigue syndrome: a case-control study. British Journal of General Practice, 2001, 51, 553-558.

CFS research has concentrated on infective, immunological, and psychological causes. Illness behaviour has received less attention, with most research studying CFS patients after diagnosis. Our previous study on the records of an insurance company showed a highly significant increase in illness reporting before development of CFS. The aim of this study was to investigate the number and type of general practitioner (GP) consultations by patients with CFS for 15 years before they develop their condition.

Design of study: Case-control study in 11 general practices in Devon. Forty-nine patients with CFS (CDC criteria '94), 40 age, sex, and general practice matched controls, and 37 patients with multiple sclerosis (MS) were identified from the general practices' computerised databases. The number of general practice consultations and symptoms recorded in three five-year periods (quinquennia) were counted before development of the patients' condition.

The median number of consultations was significantly higher for CFS patients than that of matched controls in each of the quinquennia: ratios for first quinquennium = 1.88, p=0.01; second quinquennium = 1.70, p=0.005; last quinquennium = 2.25, p=<0.001. More CFS patients than controls attended for 13 of the 18 symptoms studied^*. Significant increases were found for upper respiratory tract infection (p<0.001), lethargy (p<0.001), and vertigo (p=0.02). Similar results were found for CFS patients when compared with MS.

CFS patients consulted their GP more frequently in the 15 years before development of their condition, for a wide variety of complaints. Several possibilities may explain these findings. The results support the hypothesis that behavioural factors have a role in the aetiology of CFS.

• [* One of the listed symptoms is "illegible". Another is immunisations. Given there were no differences for symptoms associated with psychological/behavioural factors, (e.g. anxiety, depression, headaches, non-specific abdominal pain), the final sentence is not supported by the evidence actually provided by the authors. In light of the findings, the authors might have noted a vulnerability to immunological and neurological complaints.]

Jason, LA., Taylor, RR and Carrico, AW. A community based study of seasonal variation in the onset of chronic fatigue syndrome and idiopathic chronic fatigue. Chronobiological International, 2001, 18, 315-319. 

One proposed hypothesis regarding the aetiology of CFS is that there is a subgroup of patients in which symptom onset is precipitated by a viral infection.  If this is indeed true, then one would anticipate a greater incidence of the emergence of CFS symptoms during months when viral infections occur with the greatest frequency.  The current community-based epidemiology study examined the month of symptom onset for 31 patients with CFS and 44 with idiopathic chronic fatigue (ICF). It was determined that the distribution of the month of illness onset for the CFS and ICF groups was nonrandom with greater numbers of participants than expected reporting an onset of CFS and ICF during January. 

THERAPEUTICS 

Cleare, AJ., O'Keane, V and Miell J. Plasma leptin in chronic fatigue syndrome and a placebo-controlled study of the effects of low‑dose hydrocortisone on leptin secretion. Clinical Endocrinology, 2001, 55, 1, 113-9.

Previous studies have suggested that CFS is associated with changes in appetite and weight, and also with mild hypocortisolism. Because both of these features may be related to leptin metabolism, we undertook a study of leptin in CFS.

The study involved (i) a comparison of morning leptin concentration in patients with CFS and controls and (ii) a randomized, placebo-controlled crossover study of the effects of hydrocortisone on leptin levels in CFS. The sample comprised 32 medication free patients with CFS but not comorbid depression or anxiety. Thirty-two age, gender, weight, body mass index and menstrual cycle matched volunteer subjects acted as controls.

We measured basal 0900 h plasma leptin levels in patients and controls. All 32 patients were taking part in a randomized, placebo-controlled crossover trial of low dose (5 or 10 mg) hydrocortisone as a potential therapy for CFS. We measured plasma leptin after 28 days treatment with hydrocortisone and after 28 days treatment with placebo.

At baseline, there was no significant difference in plasma leptin between patients [mean 13.8, median 7.4, ng/ml] and controls (mean 10.2, median 5.5 ng/ml). Hydrocortisone treatment, for both doses combined, caused a significant increase in leptin levels compared to placebo. When the two doses were analysed separately, only 10 mg was associated with a significant effect on leptin levels. We also compared the hydrocortisone induced increase in leptin between those who were deemed treatment-responders and those deemed nonresponders. Responders showed a significantly greater hydrocortisone-induced rise in leptin than nonresponders. This association between a clinical response to hydrocortisone and a greater rise in leptin levels may indicate a greater biological effect of hydrocortisone in these subjects, perhaps due to increased glucocorticoid receptor sensitivity, which may be present in some patients with CFS.

We conclude that, while we found no evidence of alterations in leptin levels in CFS, low dose hydrocortisone therapy caused increases in plasma leptin levels, with this biological response being more marked in those CFS subjects who showed a positive therapeutic response to hydrocortisone therapy. Increases in plasma leptin levels following low dose hydrocortisone therapy may be a marker of pretreatment physiological hypocortisolism and of response to therapy.

Teitelbaum, J., Bird, B., Greenfield, R., Weiss, A., Muenz, L and Gould, L. Effective treatment of chronic fatigue syndrome and fibromyalgia. A randomized, double-blind, placebo-controlled, intent-to-treat study. Journal of Chronic Fatigue Syndrome, 2001, 8, 2, 3-28.

Hypothalamic dysfunction has been suggested in FM and CFS. This dysfunction may result in disordered sleep, subclinical hormonal deficiencies, and immunologic changes. Our previously published open trial showed that patients usually improve by using a protocol which treats all the above processes simultaneously. 

In this study, 72 FM patients (38 active: 34 placebo; 69 also met the CDC '94 criteria for CFS) received all active or all placebo therapies as a unified intervention. Patients were treated, as indicated by symptoms and/or lab testing, for: (1) subclinical thyroid, gonadal, and/or adrenal insufficiency, (2) disordered sleep, (3) suspected neurally mediated hypotension (NMH), (4) opportunistic infections, and (5) suspected nutritional deficiencies. 

At the final visit, 16 active patients were "much better," 14 "better," 2 "same," 0 "worse," and 1 "much worse" vs. 3, 9, 11, 6, and 4 in the placebo group (p<.0001). Significant improvement in the FM Impact Questionnaire (FIQ) scores (decreasing from 54.8 to 33.2 vs. 51.4 to 47.7) and visual analogue scores (improving from 176.1 to 310.3 vs. 177.1 to 211.9) (both with p<.0001 by random effects regression), and Tender Point Index (TPI) (31.7 to 15.5 vs. 35.0 to 32.3, p<.0001 by baseline adjusted linear model) were seen.

Long term follow-up (mean 1.9 years) of the active group showed continuing and increasing improvement over time, despite patients being able to discontinue most treatments. 

Using an integrated treatment  approach, effective treatment is now available for FM/CFS. 

White, PD and Naish, VAB.  Graded exercise therapy for chronic fatigue syndrome. Physiotherapy, 2001, 87, 6, 285-288.

Report on 59 patients, some with a psychiatric diagnosis, who were treated using graded exercise (GE) and other psychiatric treatments in a fatigue clinic. There is also a comparison with those included in a previously published trial. 

The drop out rate was higher (28% versus 12%). Data from 55 patients revealed that 47% had a positive outcome (rated by therapist using intention to treat analysis). The number was higher where analysis was limited to the completers only (65%, n=40). The scores for the patients were similar (47% rated themselves as having a positive outcome). Fitness increased significantly with treatment (not seen in the trial).  The mean number of sessions was 11.5. Failure to improve was linked with psychiatric illness, significant insomnia and overburdened lives. 

See also response by Shepherd, C, ibid, 2001, 87, 8, 395-396, challenging the view that graded activity is effective for the majority of patients. He cites a large survey where 50% (n=610) reported that it had made their condition worse. He also notes that the authors overlooked the evidence of neuromuscular pathology in a subgroup, and that many patients are already functioning at or near their levels of maximal physical performance. Finally, he reminds readers that there is no evidence for the widely-held assumption that deconditioning is a perpetuating factor in CFS/ME. 

MEETING ABSTRACTS

Herrel, R., Goldberg, J., Buchwald, D., Manson, S and Vega, W. Is chronic fatigue syndrome culture-bound? American Journal of Epidemiology, 2001, 153, 11 suppl., s235.

Siessmeier, T., Nix, W., Kappis, B., Landvogt, C., Schreckenberger, M and Bartenstein, P. Detection of alterations of regional cerebral glucose metabolism in chronic-fatigue-syndrome by an observer-independent analysis. Journal of Nuclear Medicine, 2001, 42 (5 SUPPL), 110P. 

REVIEWS

Natelson, BH. Chronic fatigue syndrome. JAMA, 2001, 285, 20, 2557-2559. 

Update article noting the need to study subgroups in order to identify possible organic aetiologies.

Stewart, JM. Orthostatic intolerance: a review with application to the chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome, 2001, 8, 2, 45-64.

MISCELLANEOUS

Baschetti, R. Chronic fatigue syndrome, decreased exercise capacity, and adrenal insufficiency. Archives of Internal Medicine, 2001, 161, 12, 1558-1559.

Letter discussing links between CFS and Addison disease in response to De Becker et al (ibid, 200, 160, 3270-3277). With reply by De Becker et al.

Bested, AC., Saunders, PR and Logan AC. Chronic fatigue syndrome: neurological findings may be related to blood-brain barrier permeability. Medical Hypotheses, 2001, 57, 2, 231-237. 

It is our hypothesis that altered permeability of the blood-brain barrier (BBB) may  contribute to ongoing signs and symptoms found in CFS. To support this hypothesis we have examined agents that can increase the blood-brain barrier permeability (BBBP) and those that may be involved in CFS. 

The factors which can compromise the normal BBBP in CFS include viruses, cytokines, 5-hydroxytryptamine, peroxynitrite, nitric oxide, stress, glutathione depletion, essential fatty acid deficiency, and N-methyl-D-aspartate overactivity. It is possible that breakdown of normal BBBP leads to CNS cellular dysfunction and disruptions of neuronal transmission in CFS. Abnormal changes in BBBP have been linked to a number of disorders involving the CNS;  based on review of the literature we conclude that the BBB integrity in CFS warrants investigation. 

Brunet, JL., Liaudet, AP., Later, R., Peyramond, D and Cozon GJ.

Delayed-type hypersensitivity and chronic fatigue syndrome: the usefulness of assessing T-cell activation by flow cytometry-preliminary study. Allergie et Immunologie (Paris), 2001, 33, 4, 166-172.

CFS or benign myalgic encephalomyelitis has been extensively described and investigated. Although numerous immunological abnormalities have been linked with the syndrome, none have been found to be specific. This article describes the detection of delayed-type hypersensitive responses to certain common environmental antigens in almost fifty per cent of patients with this syndrome.

Such hypersensitivity can be detected by the intradermal administration of antigens derived from commensal organisms like the yeast Candida albicans, and then monitoring for a systemic reaction over the following six to forty-eight hours. This approach can be con-solidated by performing lymphocyte activation tests in parallel and measuring in vitro T-cell activation by Candida albicans antigens by three-colour flow cytometry based on CD3, CD4 and either CD69 or CD25.

Another useful parameter is the kinetics of neopterin excretion in the urine over the course of the skin test. The results showed that the intensity of the DTH response correlated with the number of T-cells activated in vitro. Various factors have been implicated in the fatigue of many patients, notably lack of sleep. However, it remains difficult to establish causality in either one direction or the other. This work is in the spirit of a multifactorial approach to the group of conditions referred to as 'CFS'.

Chaudhuri, A. Patient education to encourage graded exercise in chronic fatigue syndrome. British Medical Journal, 2001, 322, 7301, 1545.

Letter challenging the research by Powell et al (ibid 387). With response from Bentall et al.

• [Ed. note: Other letters criticising this study were published on the eBMJ (www.bmj.com).]

Cochran, JW. Effect of Modafinil on fatigue associated with neurological illnesses. Journal of Chronic Fatigue Syndrome, 2001, 8, 2, 65-70.

Article on the beneficial effect of modafinil on fatigue reported by 21 of 25 patients with various neurological illnesses (one with CFS). 

Garralda, ME and Rangel, L.  Childhood chronic fatigue syndrome. American Journal of Psychiatry, 2001, 158, 1161.

This letter reports some results of a follow-up study on 25 adolescents with CFS and parents, seen a mean 45.5 months following the start of their illness.  Mean age at follow-up was 15 years.  Of the 25, 17 had recovered and 8 remained ill. They compared health attitudes in the patients with those of 15 healthy controls from the community.

The attributions of the patients were predominantly biological.  Parental failure to subscribe to the possibility that psychological factors could be contributing to the maintenance of the disorder was associated with poor outcome of 75% of the poor outcome group and 35% of the good outcome group (p=.02).  

In the patients, they found "unrealistic" views of normative fatigue levels.  (Fatigue levels were considered to be lower in healthy youngsters than they actually are). However, the disordered expectations were not found to be an expression of generalized overconcern about illness, pain, bodily function, and death (on the Illness Attitudes Scale). There was a tendency towards the "disease conviction" item on the scale, i.e. a belief in the presence of disease despite evidence and reassurance to the contrary.  This was more obvious in the recovered group. 

Harley, DA. Recognizing and understanding chronic fatigue syndrome: implications for rehabilitation counselors. Journal of Rehabilitation, 2001, 67, 2, 22-28.

The purpose of this article is to provide rehabilitation counsellors with an overview of the aetiology and symptomatology, as well as the diagnoses, treatment, and functional limitations of CFS. Implications and recommendations for rehabilitation counsellors are also provided.

Levin, AM. Chronic fatigue syndrome: the yeast concept. Journal of Chronic Fatigue Syndrome, 2001, 8, 2, 71-76.

Hypothesis on the role of yeast, with ideas on treatment. 

Lindstedt, G., Eggertsen, R., Sundbeck, G., Eden, S and Nystrom, E. Thyroid dysfunction and chronic fatigue. Lancet, 2001, 358, 151.

This letter reports that in 2000 adults attending primary care, there was an increasing frequency of antibodies to thyroid peroxidase when thyrotropin concentration increased from 1.0 mU/L. All patients with thyrotropin higher than 5.6 mU\L had antibodies to thyroperoxidase. "We therefore advocate that thyroid tests in primary care, such as in tired patients, include the measurement of thyrotropin and antibodies to thyroid peroxidase." 

Nishikai, M, Tomomatsu, S, Hankins RW, Takagi S, Miyachi K, Kosaka S and Akiya, K. Autoantibodies to a 68/48 kDa protein in chronic fatigue syndrome and primary fibromyalgia: a possible marker for hypersomnia and cognitive disorders. Rheumatology (Oxford), 2001, 40, 7, 806-810.

The aim of this study was to identify antinuclear antibodies (ANA) specific for CFS, and in related conditions such as FM or psychiatric disorders.

One hundred and fourteen patients with CFS (CDC '94 criteria) and 125 patients with primary and secondary FM (American College of Rheumatology) took part. As controls, healthy subjects and patients with either various psychiatric disorders or diffuse connective tissue diseases were included. Autoantibodies were examined by immunoblot utilizing HeLa cell extracts as the antigen. 

Autoantibodies to a 68/48 kDa protein were present in 13.2 and 15.6% of patients with CFS and primary FM, respectively. In addition, autoantibodies to a 45 kDa protein were found in 37.1 and 21.6% of the patients with secondary FM and psychiatric disorders, respectively. Meanwhile, these two autoantibodies were not found at all in connective tissue disease patients without FM, nor in healthy subjects (p<0.05). As a group, the anti‑68/48 kDa-positive CFS patients presented more frequently with hypersomnia (p<0.005), short‑term amnesia (p<0.07) or difficulty in concentration (p<0.05) than those CFS patients without the antibodies.

The presence of the anti‑68/48 kDa protein antibodies in a portion of both CFS and primary FM patients suggests the existence of a common immunological background. These antibodies may find utility as possible markers for a clinicoserological subset of CFS/FM patients with hypersomnia and cognitive complaints.

Pall, ML. Cobalamin used in chronic fatigue syndrome therapy is a nitric oxide scavenger. Journal of Chronic Fatigue Syndrome, 2001, 8, 2, 39-44.

Short review. 

Pall, ML. Common etiology of posttraumatic stress disorder, fibromyalgia,  CFS and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite. Medical  Hypotheses, 2001, 57, 2, 139-45 

Three types of overlap occur among the disease states CFS, FM, multiple chemical sensitivity (MCS) and post traumatic stress disorder (PTSD). They share common symptoms. 

For example, many patients meet the criteria for diagnosis for two or more of these disorders and each disorder appears to be often induced by a relatively short-term stress which is followed by a chronic pathology, suggesting that the stress may act by inducing a self‑perpetuating vicious cycle. Such a vicious cycle mechanism has been proposed to explain the aetiology of CFS and MCS, based on elevated levels of nitric oxide and its potent oxidant product, peroxynitrite.  

• [Ed. note: There are important differences between CFS and PTSD (an anxiety-related disorder which follows traumatic and life threatening events such as train crashes, fires and rape, not altered biochemistry). I am not aware of evidence of chronic pathology in PTSD such as immune activation, antibodies to various pathogens, or hypoperfusion in the brainstem. There is little evidence linking CFS with short-term stress.]

Shetzline, SE and Suhadolnik, RJ. Characterization of a 2',5'-oligoadenylate (2-5A)-dependent 37-kDa RNase L - Azido photo-affinity labeling and 2-5A-dependent activation. Journal of Biological Chemistry, 2001, 276, 26, 23707-23711.

Tarello, W. Chronic fatigue syndrome (CFS) in 15 dogs and cats with specific biochemical and microbiological anomalies. Comparative Immunology, Microbiology and Infectious Diseases, 2001, 24, 3, 165-185. 

A great deal of controversy and speculation surrounds the aetiology of CFS in human patients and the existence of a similar illness in animals. To evaluate the association with a presumptive staphilococcal infection and bacteremia, seven dogs and eight cats diagnosed with CFS (two meeting the CDC working case definition) were submitted to rapid blood cultures and fresh blood smears investigations. Nine out of 15 blood cultures proved Staph-positive and four isolates were specified as S. xilosus and S. intermedius. The presence of micrococci-like organisms in the blood was a common observation among these subjects, in association with fatigue or pain-related symptoms and biochemical abnormalities suggestive of a myopathy. Following treatment with a low dosage arsenical drug (thiacetarsamide sodium, Caparsolare, i.v., 0.1 ml/kg/ day) all patients experienced complete remission. Micrococci disappeared from the blood at post treatment controls made 10-30 days later. The outcomes were compared with those of five healthy controls and five 'sick with other illness' patients showing significant difference. 

Tarello, W. Chronic fatigue and immune dysfunction syndrome associated with Staphylococcus spp. Bacteraemia responsive to thiacetarsamide sodium in eight birds of prey. Journal of Veterinary Medicine Series B - Infectious Diseases and Veterinary Public Health, 2001, 48, 4, 267-281.

Chronic fatigue and immune dysfunction syndrome (CFIDS) is a recognized human illness with zoonotic implications that is rarely described in animals. Eight birds of prey examined between 1992 and 1995 and sharing common symptoms (asthenia, inability to fly, poor appetite and emaciation) underwent laboratory tests revealing immunodeficiency anaemia, high creatine kinase levels and low serum magnesium levels.

Diagnosis of CFIDS was based upon these features. The effectiveness of an arsenic‑based medication, thiacetarsamide sodium, administered intravenously for 2‑3 days at low dosages (0.1 ml/kg/day) has been demonstrated by checks carried out 10, 20 and 30 days after therapy. The symptoms and the immune and haematological dysfunctions disappeared within 2-4 weeks of treatment. In all patients, micrococcus-like organisms found adhering to the outer surface of many red blood cells, had disappeared at post-treatment controls. Two of five blood cultures were positive for Staphylococcus spp. (S. intermedius and S. xilosus). Consideration is given to the pharmacological activity of an arsenic‑based drug in animal illnesses resembling CFIDS.

Van der Eb, CW and Jason, LA. Chronic fatigue syndrome: assessing symptoms and activity levels for treatment planning. Directions in Clinical and Counseling Psychology. Long Island City, NY: Hatherleigh Co., Ltd, (pp. 125-135)

Current approaches to diagnosis and assessment of CFS pose methodological problems that obscure not only the complexities and dynamic interrelations among a patient's symptoms but also the enormous variability of CFS symptoms from one patient to another. A survey of empirical research and case studies suggests that a more fruitful approach for the clinician involves use of self-report rating scales designed for CFS diagnosis and assessment in combination with an instrument that measures frequency and intensity of physical activity. Application of this dual approach measurement system is discussed in the context of treatment planning and implementation.

Van Rensburg, SJ., Potocnik, FC., Kiss, T., Hugo, F., van Zijl, P., Mansvelt, E., Carstens, ME., Theodorou, P., Hurly, PR., Emsley, RA and Taljaard JJ. Serum concentrations of some metals and steroids in patients with chronic fatigue syndrome with reference to neurological and cognitive abnormalities. Brain Research Bulletin, 2001, 55, 2, 319-325.

Symptoms of CFS include disturbances of cognition. Certain factors have in the past been shown to influence cognition, including metals such as aluminum, iron, and zinc; and steroids such as dehydroepiandrosterone.

In the present study, concentrations of these factors were determined in the serum and plasma of patients with CFS (CDC criteria '92) and their age- and gender-matched healthy controls (10 women and 5 men in each group). In addition, copper, dehydroepiandrosterone sulphate, cortisol, cholesterol, haemoglobin, ferritin and transferrin concentrations, as well as transferrin genetic subtypes were determined in both groups.

The results indicate that patients had significantly increased serum aluminum and decreased iron compared to controls. In the females, serum iron and dehydroepiandrosterone sulphate were significantly decreased and correlated. Total cholesterol was significantly increased, and significantly negatively correlated with dehydroepiandrosterone sulphate.

There were no differences in zinc, copper, cortisol, haemoglobin, transferrin and ferritin concentrations, or in transferring genetic subtypes.

Various. Cognitive behaviour therapy for chronic fatigue syndrome. Lancet, 2001, 358, 238-241. (Letters).

Chaudhuri (p. 238) responding to the paper by Prins et al (ibid, 357, 841), questions the variability in the number of patients used in the statistical analysis as well as the reliability of the conclusions.  Vermeulen et al (p. 238-9) focus on the failure to select patients according to the CDC criteria and the limited data. Shepherd (p. 239) asks if this type of expensive and difficult to obtain hospital‑based treatment is any more effective than active management in a primary-care situation? This comparison is .... not measured by Prins and colleagues...

"Family physicians and members of primary‑care health teams who are competent at assessing and managing CFS patients are capable of providing advice about the need to balance rest with appropriate increases in activity, symptomatic relief for pain, sleep disturbances and so on, guidance on education and employment, social benefits, &c, and access to providers of disability services and social support. All these factors are relevant to the recovery process in CFS, and it is astonishing that the only forms of outcome comparison done by Prins and colleagues were groups who received non-directive support from social workers, or who were left to follow a natural course with no interventions."

According to Shepherd, this continued failure to obtain information on the outcome of patients receiving active management in primary care has important logistical and cost implications for service providers. The minimum prevalence of CFS is around 0.4% of adults (ie, up to 200 000) in the UK; there are too few therapists to take on this extra work-load. Even if there were enough, the cost to the National Health Service, at more than 1000 pounds per course of CBT, would be prohibitive.

Prins and colleagues conclude that CBT could be successfully and effectively administered by therapists with no previous experience in CBT (did they mean CFS?). This finding is in contrast to results obtained from a questionnaire on treatment outcomes. Of 2338 respondents, 285 had received CBT. Only 21 of 285 (7.4%) found CBT helpful, whereas 191 of 285 (67%) reported no change. 26% of respondents thought their disorder worsened after CBT. This survey supports the view that CFS is a heterogeneous illness in clinical presentation and possible cause. Although the purely psychosomatic explanation favoured by Prins and colleagues might apply to a subgroup of patients with CFS, other cases with neurological, muscular, and endocrine abnormalities cannot be adequately explained by this model. Underlying organic pathology might help to explain why those who do benefit from CBT improve only slightly, with objective evidence of more substantial and sustained recovery (ie, return to normal employment) being rare.

Lassesen (p. 239) challenges the long term effects, citing a report from a conference suggesting the benefits tend to be temporary. He also alludes to other treatments which may be appropriate for some patients. Spence and Abbot (p. 239-240) acknowledge that CBT may be helpful for a subgroup but that generalisation about the population as a whole is not justified. Baschetti (p. 240) discusses the links with hypocorticolism. 

The authors reply (p. 240-241) that they assessed additional symptoms at baseline and found that 252 patients met the criteria for CFS while 18 had idiopathic chronic fatigue. They claim that the fatigue and impairment scores indicated severe disability and that CBT is always linked with graded activity. They allude to several studies indicating that this is a helpful approach for CFS and to a one five-year follow-up (Deale et al, in press). 

• [Ed. note: The authors' reply includes misleading comments. CBT can be offered independently of graded activity e.g. Friedberg and Krupp 1994. The Karnofsky scores indicate that not all subjects were severely impaired. The five-year follow-up indicates that the group differences were not maintained on all measures.] 

Wessely, S.  Chronic fatigue syndrome: symptom and syndrome. Annals of Internal Medicine, 2001, 134, 9 (Suppl.), 838-843.

Discussion on fatigue and CFS, suggesting that some of the desire to split the CFS into subgroups "is driven by emotion" and that a division  will "neatly separate physical and psychological causes".

• [Ed. note: this is a highly selective discussion of CFS, with the suggestion that those who regard subgrouping to be useful are motivated not so much by evidence and science as by emotional and simplistic thinking. There is no mention of the evidence supporting the subgrouping e.g. of ME.] 

See also Aaron, LA and Buchwald, D. A review of the evidence for overlap among unexplained clinical conditions. Ibid, 2001, 134, 868-881. With editorial by Komaroff, AL (ibid, 134, 783-785).

RESEARCH ON OTHER DISORDERS

Forton, DM., Allsop, JM., Main, J., Foster, GR., Thomas, HC and Taylor-Robinson, SD. Evidence for a cerebral effect of the hepatitis C virus. Lancet, 2001, 358, 38-39.

This letter reports the results of MRI scans on 30 patients with hepatitis C, 12 with hepatitis B and 29 healthy controls.  They found elevations in basal ganglia and white matter choline/creatine ratios in patients with histologically-mild hepatitis C compared with the other two groups.  This elevation suggests that a biological process underlies the extra-hepatic symptoms in chronic HCV infection (listed symptoms include fatigue, lassitude, brainfog).

BOOK REVIEW^*

Richardson, J. Enteroviral and toxin mediated myalgic encephalomyelitis/chronic fatigue syndrome and other organ pathologies. New York, Haworth Press. Pb 247pp. £21.68.

A book on the effects of viral infections, including ME. Aimed at physicians and scientists. 

CORRECTION

This replaces the summary published previously.

Cox DL and Findley, LJ. Severe and very severe patients with chronic fatigue syndrome: perceived outcome following an inpatient programme. Journal of Chronic Fatigue Syndrome, 2000, 7, 3, 33-47.

This is a report of an in-patient programme featuring CBT, gentle graded activity and occupational therapy, for severe and very severely affected patients with CFS.  Seventy-two patients were followed of whom 32 had CFS. In this group, 81% reported improved activity 6 months following discharge while no one felt worse. The period in hospital ranged from 4 to 10 weeks.  Seven other patients had CFS plus additional problems and 33 of the total group received an alternative diagnosis during their stay.

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

Sources used include ISI Personal Alert, Co-Cure and Medline. With thanks to Dr. Marc Fluks. Drs Trudie Doorduin and Mrs. Sandra Howes.

E-mail: ellengoudsmit@hotmail.com or david.axford@virgin.net

This is a private educational resource. Please do not reproduce without permission from the editor. Although every effort is made to limit errors, we recommend that readers use the information above as a guide only.  

Copyright EM. Goudsmit 2001. ©
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