GUIDELINES FOR EVALUATING AND DEFINING CFS, K. FUKUDA Mall Stop A 15, Atlanta, USA

In 1994, a group of international researchers and clinicians published guidelines (Ann. Intern. Med., 1994, 121 : 953 - 9) that contained steps for evaluating cases of unexplained fatigue and revised criteria for defining chronic fatigue syndrome (CFS).

The overall objectives were 1) to clarify the steps necessary for evaluating fatigued persons, 2) to improve the collection of information on CFS and related disorders in formal studies, and 3) to modify CFS-defining criteria on the basis of experience accumulated since 1988.

The guidelines cover the clinical evaluation in detail, including the appropriate and inappropriate use of laboratory tests. They also provide principles for identifying the medical and psychiatric conditions that should excluse the diagnosis of CFS and those conditions that should not.

The revised CFS case definition, which was modeled after the 1988 definition by Holmes et al. (Ann. lntem. Med., 1988, 108: 387 -9), is intended to consolidate different international approaches. Modifications of the 1988 case definition include removal of all physical signs and a reduction in the number of symptoms as criteria.

For researchers, a conceptual framework, an approach to subgrouping study participants, and examples of standardized instruments to aid in the collection of data are provided.

MULTI-DIMENSIONAL ASSESSMENT IN CHRONIC FATIGUE SYNDROME - J.H.H.M. VERCOULEN (1), E. BAZELMANS (1), C.M.A. SWANINK (2.3), J.F.M. FENNIS (2), J.M.D. GALAMA (3), J.W.M. VAN DER MEER (2), G. BLEIJENBERG

1 Dept. of Medical Psychology, University Hospital Nijmegen, The Netherlands
2 Dept. of General Internal Medicine, University Hospital Nijmegen, The Netherlands
3 Dept. of Medical Microbiology, University Hospital Nijmegen, The Netherlands

Fatigue is a subjective and nonspecific complaint and is thus difficult to define or measure. Our research group has developed a multidimensional assessment method.

In a study in 298 CFS patients behavioural, cognitive, emotional, and social aspects were measured by questionnaires. Factor analyses yielded 9 dimensions : psychological well-being, level of physical activity, functional impairment, sleep problems, neuropsychological problems, social functioning, attributions regarding the causes of the complaints, and self-efficacy expectations, and the subjective experience of fatigue.

These dimensions proved to be relatively independent. This means that each dimension provides a unique contribution to the description of the patient. These dimensions should be measured by different methods of assessment. We use questionnaires, a 12-day self-observation list, standardized neuropsychological tests, and a motion-device measuring physical activity.

THE 1995 CLASSIFICATION CRITERIA FOR CHRONIC FATIGUE SYNDROME  A. HOFFMANN (1), R. LINDER (1), B. KROEGER (2), G.R.F. KRUEGER (2,3), W.L. GROSS (1)

1 Medical University of Luebeck, Dept. of Rheumatology, Germany
2 University of Cologne, Dept. of lmmunopathology, Germany
3 International Institute of Immunopathology, Cologne, Germany, Houston, Mexico

INTRODUCTION : the following classification criteria (CC) for chronic fatigue syndrome (CFS) were based upon a prospective randomized multi-centre longitudinal study of 198 patients (P) with severe fatigue for over 6 months. For first time the statistical value was determined of CFS-symptoms by comparing them with a control group consisting with severe fatigue but well known different underlying disease, namely fibromyalgia (FMA) and systemic lupus erythematosus (SLE).

METHODS: the CC-CFS were determined according to the recommendations of the American College of Rheumatology (ACR) using a collective of 158 randomized (P) (CFS : n = 79, m:w 38:41, median 41,8 years (y); FMA : n = 54, m:w 8:46, median 50,7 y; SLE: n = 25, m:w 3: 22, median 49,6 y). These include (CC) in the traditional format (TFC), regression coefficient criteria (RCC) and regression tree criteria (RTC). A validation of CC-CFS was undertaken with a collective of further 40 (P) (CFS : n = 20, m:w 9:11, median 41,7 y; FMA: n = 4, m:w 1:3, median 52,0 y; SLE: n = 16, m:w 4:12, median 48,1 y), which had not been used for the generation of the criteria. A comparison to the CDC-criteria was under-taken.

RESULTS : the CC-CFS were shown to be easy to apply and to have comparable specificities (SP), sensitivities (SE) and accuracies (A) of over 90 % for each of the different formats in comparison to the CDC-criteria and this was demonstrated in the validation (-V) :

CDC SE 62,6% SP 93,9% A 78,3% CDC-V SE 50,0% SP 75,0% A 62,5% TFC SE 93,7% SP 94,9% A 94,3% TFC-V SE 90,0% SP 65,0% A 77,5% RCC SE 96,2% SP 98,7% A 97,5% RCC-V SE 90,0% SP 75,0% A 82,5% RTC SE 98,7% SP 98,7% A 98,7% RTC-V SE 80,0% SP 85,0% A 82,5%

Sudden onset of fatigue and sore throat were demonstrated to be the most discriminative symptoms in CFS.

CONCLUSION : using only clinical data the CC-CFS allow a reliable and valid classification of CFS with a well characterised symptomatology, which suggests an infectious aetiology in CFS.
 
 

NEUROENDOCRINOLOGY OF CHRONIC FATIGUE SYNDROME, T.G. DINAN Department of Psychological Medicine, St. Bartholomew's and Royal London Hospital Medical School, United Kingdom

There is an increasing volume of evidence to support the view that chronic fatigue syndrome (CFS) has a unique endocrinology. Central to this endocrine dysfunction is altered hypothalamic-pituitary-adrenal axis (HPA) activity. This might be triggered by a wide range of stressors either physical or psychological. Studies examining both forward regulation and fast-feedback inhibition of the HPA will be presented. In a study of 14 patients with CFS and 14 age and sex matched comparison subjects ipsapirone, the 5HT1a partial agonist, was used to stimulate ACTH release. Baseline ACTH and cortisol levels did not differ between the 2 groups. Release of ACTH in response to ipsapirone challenge was blunted. This may be caused by an abnormality in the 5HT1a receptor.

We have shown in healthy subjects that fast-feedback inhibition of the HPA is mediated by a type 2 giucocorticoid receptor and not a type 1 mineralocorticoid receptor. By infusing hydrocortisone intravenously and examining changes in ACTH levels we have compared fast-feedback responses in patients with CFS, depression and healthy comparison subjects. The CFS patient group showed a significant attenuation in the ACTH decrease following hydrocortisone. This suggests there may be a disturbance at a glucocorticoid receptor level.

The manner in which 5HT and giucocorticoids might interact at a pathophysiological level will be discussed.

DEMOGRAPHIC DATA ON PATIENTS WITH CHRONIC FATIGUE SYNDROME AT A UNIVERSITY HOSPITAL IN STOCKHOLM ,B. EVENGARD, G. LINDH, L. LINDQVIST, R. OLIN

Division of Infectious Diseases, Karolinska Institute at Huddinge University Hospital, Stockholm, Sweden

OBJECTIVES : since three years we have an outpatient department for patients with chronic fatigue syndrome. We wanted to analyse basic demographic data on these patients in order to further stratify the population for more focused studies.

METHODS : before coming to the unit the patients filled in a questionnaire which included sex, age, socioeconomic factors, medical history, symptoms during time and their own belief about the cause.

RESULTS : preliminary analysis shows that in November 1994, 289 patients had been investigated. 62 % of the patients were female. 93 fulfilled the criteria (Holmes et al., 1988). Of these 78 % were women. The median duration of illness was 2.6 years.

In June 1995 we had investigated a total of 362 patients, 65 % women, and 163 fulfilled criteria which since the beginning of 1995 are the new CDC-criterias (Fukuda et al.). Of these 72 % are women.

We get 34 % of the patients on referrals from general practitioners and 28 % from other hospitals. In November 1994 33 % of the patients we accepted (all referrals are discussed) fulfilled criteria while in June 1995 45 % did. An infectious disease onset was found in 58 %.

PRELIMINARY EVIDENCE FOR A MOLECULAR BASIS TO CHRONIC FATIGUE SYNDROME, N.R. MCGREGOR (1), R.H. DUNSTAN (2). M. ZERBES (2), H.I. BUTT (3), T.K. ROBERTS (2) I.J. KLINEBERG (1)

1 Neurobiology Research Unit, Centre for Oral Health Research, University of Sydney, Westmead Hospital, Australia
2 Dept. of Biological Sciences, The University of Newcastle, Callaghan, Australia
3 Division of Microbiology and Infectious Diseases, John Hunter Hospital, New lambton Heights, Australia

Chronic fatigue syndrome (CFS/ME) is a debilitating fatigue illness that has an unknown aetiology. We studied 20 chronic fatigue syndrome (CFS) patients, who complied with the Oxford and American CDC definitions, and 45 non-CFS subjects.

Participants completed questionnaires, were clinically examined and had first morning urine specimens collected, which were screened by gas chromatography - mass spectrometry for changes in metabolise excretion.

Multivariate analysis of the urinary metabolise profiles differed significantly in the CFS patients compared to the non-CFS patients (p < 0.004). The CFS patients had increases in amino-hydroxy-N-methyl- pyrrolidine (p < 0.00003, referred to as chronic fatigue symptom urinary marker 1, or CFSUM1), tyrosine (p < 0.02), b-alanine (p < 0.02), aconitic acid (p < 0.05) and succinic acid (p<0.05) and reductions in an unidentified urinary metabolise, CFSUM2 (p < 0.0007), alanine (p < 0.005) and glutamic acid (p < 0.02). CFSUM1, b-alanine and CFSUM2 were found by discriminant function analysis to be the 1st, 2nd and 3rd most important metabolises, respectively, for discriminating between CFS and non-CFS subjects.

The abundances of CFSUM1 and b-alanine were positively correlated with symptom incidence (p < 0.01 and p < 0.001, respectively), symptom severity, core CFS symptoms and SCL-90-R somatization (p < 0.00001) suggesting a molecular basis for CFS in this cohort.

DEFECTIVE DEXAMETHASONE INDUCED GROWTH HORMONE RELEASE IN CHRONIC FATIGUE SYNDROME - EVIDENVE FOR CEREBRAL GLUCOCORTICOID RECEPTOR RESISTANCE, T.MAJEED (1), T.G. DINAN (2), P.O. BEHAN (1)

1 University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, United Kingdom
2 Department of Psychological Medicine, St Bartholomew's Hospital, United Kingdom

OBJECTIVES : recent evidence has suggested impaired activation of HPA-axis in patients with chronic fatigue syndrome. This study was designed to examine the functional interaction between the HPA-axis and the hypothalamic-somatotrope axis by stimulating the central steroid receptors with synthetic glucocorticoid and measuring growth hormone responses.

METHODS : twelve patients (six males and six females) who fulfilled the CDC criteria for chronic fatigue syndrome and twelve healthy sex and age matched subjects were examined in this study. The test was carried out in two phases and commenced in the morning following an overnight fast. In the first phase dexamethasone 4 mg orally was given at 0 min and samples were taken at 0, +60, +90, +120 and + 180 and 240 min for growth hormone measurement. In the second phase of the study, after a week's interval, the same patients were given metyrapone 500 mg six hourly for 24 hours and then the dexamethasone test was repeated as in the first phase.

RESULTS : growth hormone response to dexamethasone (DGH) was calculated as the maximum GH level post dexamethasone, relative to baseline. In Phase I DGH values were CFS, 3.22 # 1.26 and controls 19.20 # 2.07 and Phase II, 4.93 # 1.63 and controls 26.98 # 4.12. The response seen in CFS was significantly lower than in healthy individuals.

CONCLUSION : growth hormone response to dexamethasone before and even after metyrapone when steroid receptors were unregulated, was blunted in patients with CFS suggesting seroid receptor resistance or lack of plasticity. Is this resistance responsible for impaired activation of HPA-axis ?
 
 

MUSCLE STUDIES IN CHRONIC FATIGUE SYNDROME , W.M.H. BEHAN

Department of Pathology, University of Glasgow, Scotland, UK

Although fatigue and myaigia are such important components of CFS, it is difficult to identify consistent muscle morphological and functional abnormalities. No specific histological or histochemical findings are detected but some cases show ultrastructural changes similar to those in mitochondrial myopathies.

Tests of aerobic capacity have produced controversial results. Evaluation of muscle metabolism before and during exercise using 31P nuclear magnetic resonance spectroscopy however, showed clear differences between patients and controls. We have carried out a carefully controlled isokinetic dynamometry study to elucidate the problem.

We have also studied oxidative metabolism and respiratory capacity in cultured myoblasts from patients with CFS. Two subsets were identified : one had a high lactate to pyruvate ratio while the other had an unusually low ratio indicating normal oxidative phosphorylation but a possible decrease in flux through glycolysis. Each of these changes would result in a decreased ability to maintain an appropriate ATP/ADP ratio and concomitant fatigue made worse by exertion.

Since changes in the mitochondrial genome are associated with dysfunction we examined patients' muscle biopsies for deletions in mitochondrial (mt) DNA. Preliminary studies revealed 2 of 8 cases were positive for the mt 4977bp "common" deletion, on polymerase chain reaction, using specific primers. In one of these, the deleted mtDNA represented 21 % of the total: a level which would be expected to have functional consequences. A larger study is being carried out. The pattern of muscle abnormalities detected suggests CFS is a heterogenous disorder in which some patients.

IDENTIFICATION OF ENTEROVIRAL RNA DETECTED IN MUSCLE BIOPSIES FROM PATIENTS WITH MYOSITIS OR CHRONIC FATIGUE SYNDROME USING REVERSE TRANSCRIPTION, NESTED POLYMERASE CHAIN REACTION AND NUCELOTIDE SEQUENCING , B.SOTERIOU (1), H.Y. ZHANG (1), D.R. WOODROW (2), R.J.M. LANE (1), L.C. ARCHARD (1)

1 Department of Biochemistry, Charing Cross & Westminster Medical School, U.K.
2 Department of Histopathology, U.K.
3 Department of Neurology, Charing Cross Hospital, U.K.

Skeletal muscle biopsies were investigated for the presence of enterovirus RNA sequences by reverse transcription, nested polymerase chain reaction (RT-NPCR).

A proportion of these patients had a histologicaiiy-proven diagnosis of myositis and some had Chronic Fatigue Syndrome. We used group-specific PCR primers, capable of amplifying sequences from a wide range of enterovirus serotypes. A proportion (3/13) of muscle samples from these cases were positive for enterovirus sequences by RT-NPCR, while all 20 normal muscle samples in the comparison group were negative. Direct nucleotide sequencing of NPCR products permitted the identification of the enterovirus serotype involved, which was most closely related to Coxsackie virus B3 (CVB3) in each case. Of the 3 PCR positives, 2 showed an identical nucleotide sequence to CVB3 strain Nancy within this region of the genome while the third differed by one nucleotide.

These data suggest an association between enterovirus infection and skeletal muscle disease, analogous to that seen in dilated cardiomyopathy (Khan et al., 1994, Biochem. Trans. Soc. 22, p. 176 s).

ALTERATIONS IN MUSCLES OF CFS PATIENTS AT MORPHOLOGICAL BIOCHEMICAL AND MOLECULAR LEVEL - E. PIZZIGALL0 (1), A. DI GIROLAMO (1), G. MONTANARI (2), L. DRAGANI (2), J. VECCHIET (2)

1 Clinic of Infectious Disease, *G. D'Annunzio* University, Italy
2 Institute of Medical Physiopathology, *G. D'Annunzio* University, Italy

OBJECTIVES : the peripheral origin of symptoms related to CFS has been hypothesized from various AA and is still under investigation if symptoms can be related to a muscular damage. Our studies aimed to look for specific alterations in muscles of CFS patients, followed in our Clinic and enrolled according to the 1988 CDC criteria (Holmes and coil.), revised in 1994 by Fukuda and coll. (CDC).

METHODS : 14 CFS patients, 3 males and 11 females, 17 to 60 years old (mean 34.6 years), mean illness duration 49.9 months, post viral onset in 10 cases, underwent muscular biopsy of the vastus lateralis according to Edwards and coll., using a UCH needle. We analyzed the specimens by electron (EM) and light (LM) microscopy. Moreover we performed histochemical and quantitative analysis of enzymatic activities and studies of mitochondrial DNA (mtDNA) deletions.

RESULTS : all specimens showed : hypotrophy, especially of the type II (a and b) fibres; fibres fragmentation, red ragged fibres and fusion events with nuclei centralisation; fatty and fibrous degeneration. EM observations confirmed these alterations, showed degenerative changes in the I band, and allowed us to detect the poli/pleiomorphism and cristae thickening of the mitochondria. The alterations of the fibres always begin from an I band of a sarchomer. The hystochemical and quantitative determination of the enzymatic activities showed important reduction, in particular of the cytochrome-oxydase and citratesyntetase. Finally, the "common deletion" of 4977 bp of the mtDNA was increased as high as 3000 times the normal values in 3 patients.

CONCLUSIONS : our results agree with those of other AA (Behan et al., 1991; Gow et al., 1994). The alterations are compatible with a myopathy of probable mitochondrial origin. This could explain the drop in the functional capability of the muscle as a reduction in potency but, above all, as a reduction in resistance. In conclusion, even if CFS seems to be attributable to mitochondrial and/or muscular alterations, a damage in the central nervous system cannot be excluded. This could explain the neuropsychological, behavioural, and neuroendocrinological alterations often found in these patients.
 
 

POLIOENCEPHALITIS, DOPAMINE AND THE BRAIN FATIGUE GENERATOR HYPOTHESIS OF POST-VIRAL FATIGUE SYNDROMES - R. BRUNO

Kessler Institute for Rehabilitation, Post-Polio Service, New Jersey, U.S.A.

Fatigue is the most commonly reported and most debilitating Post-Polio Sequelae (PPS) affecting millions of polio survivors world-wide. Post-polio fatigue is associated with : 1) subjective reports of difficulty with attention, cognition, word-finding and maintaining wakefulness; 2) clinically significant deficits on neuropsychological tests of information processing speed and attention; 3) gray and white matter hyperintensities in the reticular activating system on magnetic resonance imaging of the brain; 4) neuroendocrine evidence of impaired activation of the HPA axis.

Many of these findings are identical to those documented following a variety of viral encephalidities, including acute poliovirus infection, lethargic encephalitis, Iceland Disease, myalgic encephalomyeiitis, and, most recently, Chronic Fatigue Syndrome.

The clinical, historic, neuropsychologic, neuroanatomic and physiologic parallels between poliovirus infection, post-polio fatigue syndromes (PFS) will be explored in an attempt to describe the pathophysiology of PFS. The disinhibition of a putative Brain Fatigue Generator will be implicated as a cause of the subjective symptoms and objective signs that accompany PFS.

The results of a placebo-controlled study of a dopamine2 receptor agonist to treat post-polio fatigue will also be described.

EXERCISE CAPACITY IN POST-POLIO PATIENTS - A.BEELEN (1,2), F. NOLLETI (1), A.J. SARGEANT (2)

1 Department of Rehabilitation, Academic Medical Centre, Vrije Universitelt, Amsterdam, The Netherlands
2 Department of Muscle and Exercise Physiology, Vrije Universiteit, Amsterdam, The Netherlands

Many people previously affected by polio experience new muscular symptoms decades after the initial illness. These new symptoms include increased fatigue, muscle weakness and are usually referred to as the "postpolio syndrome (PPS)". The pathophysiologic basis remains unclear but chronic overload by performing normal activities of daily living has been proposed as one, of the factors involved.

In the present study we examined exercise capacity in a group of 40 subjects who had polio and in a group of 13 healthy control subjects of the same age who never had polio (mean age (SD) was 45.2 yrs. (8.4)). From the 40 subjects with polio 24 subjects fulfilled the criteria of PPS [mean age 45.0 yrs (6.0), leaving 16 polio-controls (mean age 45.7 yrs. (5.8)].

An incremental exercise test (4 min steps of 25-50 W) was performed at a pedal rate of 70 rev/min on an electrically braked cycle ergometer with force transducers in the pedals. The test ended when subjects reached a heart rate of 80 % of their predicted heart rate reserve (HRR). Oxygen uptake was measured continuously and expressed as the percent difference from the predicted normal value of oxygen uptake for the given power and gender according to Astrand (Acta Physiol. Scand. 49, suppl. 169, 1960).

The mean power (SD) produced at 80 % HRR in the PPS group was 76 W (25), not significantly different from 86 W (25) in the polio-controls. The mean power in the control group was 153 W (33) and this was significantly higher than the values for the polio groups (p < 0.001, ANOVA). The percent difference in oxygen uptake was significantly larger in the polio groups compared with the normal control subjects [PPS group + 16.6 % (15.9); polio-controls + 20.9 % (22.2) and normal control subjects + 3.6 % (6.8), p < 0.05].

These findings suggest that exercise capacity in post-polio patients is reduced to a large extent compared to healthy control subjects of the same age. In order to perform similar activities of daily living post-polio patients will be required to work at higher relative levels of effort which may lead to greater fatigue. The larger percent difference in oxygen uptake may represent a further limitation on sustained locomotion in this patient group.

This work was supported by the 'Prinses Beatrix Fonds', The Hague, The Netherlands.
 
 

MICROBIAL PATHOGENS AS CAUSE OF CFS -J.M.D. GALAMA (1), C.M.A. SWANINK (1), J.H.H.M. VERCOULEN (2), J.F.M. FENNIS (2.3), G. BLEIJENBERG (2), J.W.M. VAN DER MEER (3)

1 Dept. of General Internal Medicine, University Hospital Nijmegen, The Netherlands
2 Dept. of Medical Psychology, University Hospital Nijmegen, The Netherlands
3 Dept. of Medical Microbiology, University Hospital Nijmegen, The Netherlands

CFS patients frequently report that their symptoms started with a flu-like illness. This made that patients as well as many professionals became convinced that microbial pathogens are causally involved in CFS. Microbial pathogens are well known for causing fatigue, mainly by activating the host defence mechanisms. Chronic hepatitis B or C infections for example can go with a debilitating fatigue and giardiasis can also cause complaints resembling CFS.

Since infections are an established cause of fatigue, their diagnosis will exclude them - by definition - as a direct cause of CFS. Therefore investigators have focused on unorthodox manifestations of infections. Examples are chronic but culture-negative Brucelia infection, chronic Epstein-Barr virus infection, chronic culture-negative enterovirus infection, retrovirus infection. To increase sensitivity new diagnostic tests were applied, such as the VP1 test, slotblot hybridization and PCR. Antibody levels were compared between individuals. Lymphocyte phenotypes and cytokine levels were scrutinized for signs of immune activation.

The fruits of all these studies are many conflicting reports. An overview will be given and possible cause for discrepant outcomes will be discussed.

BORNA DISEASE VIRUS IN THE ATLANTA CFS CASE-CONTROL STUDY - J.G. DOBBINS (1), W.I. LIPKIN (2), C. EVEN (2), A.C. MAWLE (1)

1 CDC, Atlanta, USA
2 Univ of California, lrvine, USA

OBJECTIVE : to determine the prevalence of Borna disease virus (BDV) antibody seropositivity among CFS cases and controls.

METHODS : All 26 CFS cases in the Atlanta CFS surveillance study who met the 1988 case definition were enrolled in a seroepidemiologic study to identify immunologic and behavioral variables that might be related to the presence of disease. Each case was matched with two randomly selected community controls on the basis of race, sex, and age. Serum from these 26 cases and 46 of their matched controls were tested by ELISA for the presence of BDV antibodies against three recombinant proteins : p40 (nucleoprotein), p23 (phosphoprotein), and gp18 (matrix protein). lmmunoreactivity to these proteins was also tested by Western blot. In addition, sera were tested for non-specific reaction to bovine serum albumin (BSA). Subjects with a positive ELISA test for any of the three proteins and a negative test for BSA were considered positive for BDV.

RESULTS: serum from three (11.5 %) of the CFS cases and none (0.0 %) of the controls were positive by ELISA for BDV (p = 0.044). Serum from two of these three cases reacted with all three BDV proteins; the third reacted only with p23. Six additional sera (23 %) reacted with one or more of the BDV proteins but also reacted with BSA. Five of these six specimens were from controls, one from a case.

DISCUSSION : these results indicate that BDV may be associated with a small but significant portion of CFS cases. Our results are high compared with two other studies in which all subjects were negative, but below the results of a Japanese study (presented at this meeting) where 34 % of the subjects' sera reacted to BDV phosphoprotein. Further testing in other locations using a standard protocol is warranted.

DEMONSTRATION OF BORNA DISEASE VIRUS RNA IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM JAPANESE PATIENTS WITH CFS - K.IKUTA (1), T. NAKAYAI (1), H. TAKAHASHI (1), Y. NAKAMURA (1), S.ASAHI (1), M. TOBIUME (1), H.KURATSUNE (2), K. YAMAGUTI (2), R.INAG1 (3), K. YAMANISHI (3), T. KITANI (2)

1 lnstititute of immunological Science, Hokkaido University
2 Dept. of Hematoly & Oncology, Hokkaido University
3 Dept. of Microbiology, Osaka University School of Medicine, Japan

Borna disease virus (BDV) is a neurotropic, yet unclassified, nonsegmented, negativesense, single-stranded RNA virus which naturally infects horses and sheep. Several reports showed a significantly higher seroprevalence of BDV in psychiatric patients, compared with healthy controls. Recently, we have developed a nested RT-PCR using primers for the BDV p24 gene to detect successfully the genetic footprints of BDV in PBMCs derived from psychiatric patients. As high as 36.7 % examined showed positive reaction in psychiatric patients in our examination, while the same technique showed only 4.7 % prevalence in PBMCs derived from healthy blood donors.

Here, we centered on the possible link between CFS and BDV infection. First, we studied BDV seroprevelance of 89 Japanese who were diagnosed with CFS in accordance with guideline established by the CDC. Controls were 1 00 healthy donors. The results showed significantly higher seroprevalence of BDV in CFS compared with the controls. The seroprevalence of BDV in CFS was similar as psychiatric patients. Second, we studied BDV RNA in PBMCs from CFS patients by nested RT-PCR followed by hybridization. The results showed that BDV RNA was detected as a clear signal in 2 and a weak signal in another 2 out of 13 patients. In the p24 region of the genome, the sequences of the apparent signals from 2 patients showed 2 - 9 % and 3 - 11 % intra-patient divergencies and 13 - 22 % inter-patient divergency in the amino acid level which was rather higher than the divergencies between CFS- and horse-derived BDVS. Thus, our results suggest that Japanese CFS is associated, at least in part, with active infection of BDV, or BDV-related agent.

FAILURE TO DEMONSTRATE ENTEROVIRUS IN SWEDISH PATIENTS WITH THE CHRONIC FATIGUE SYNDROME - G. LINDHI (1), A. SAMUELSSON (2) , K-O HEDLUND (2), B. EVENGARD (1), L. LINDQVIST (1), A. EHRNST (2)

1 Dept. of Immunology, Microbiology, Pathology and Infectious Diseases, Division of Infecticius Diseases, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden
2 Dept. of Immunology, Microbiology, Pathology and Infectious Diseases, Division of Clinical Virology, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden

A special unit for patients with the chronic fatigue syndrome started in 1992 at the Department of Infectious Diseases at Huddinge Hospital, Sweden. As most of our patients had a flu-like episode at onset of their illness and initially a relationship with enteroviruses was suspected the following study was undertaken.

PATIENTS: thirtyfour patients (22 women, 12 men) meeting the CDC criteria for the chronic fatigue syndrome (CFS) by Holmes et al. 1988 (Chronic Fatigue Syndrome. A working case definition, Ann. Intern. Med., 1988; 109: 387-9) were included in the study. Mean age at onset of illness was 35 (range 19 - 54, median 34) years. All 34 patients had a history of infectious disease at onset. Mean duration of illness at diagnosis was 2.7 (0.5 - 7, median 2.0) years. Fifty percent (17/34) had pronounced muscle symptoms, including post-exertional fatigue and 18/34 (53 %) showed pronounced neuropsychiatric symptoms.

MATERIALS and METHODS : in 12 patients 1-5 faecal samples were collected for acid treatment followed by ultra centrifugation and isolation at about 4 months interval. Another 14 faecal samples were subjected to routine virus isolation alone. Paired serum and cerebrospinal fluid (CFS) samples were collected from 7 patients. In 29 patients a muscle biopsy was performed. The faecal samples were processed as described by Yousef et al. 1988 (Yousef et al., Chronic enterovirus infection in patients with postviral fatigue syndrome. The Lancet, 1988; 146-7) and also analysed by direct electron-microscopy and after airfuge centrifugation. The 7 serum-CFS samples were analysed for cross-reactive LgG antibody activity to enteroviruses. A polymerase chain reaction protocol for enterovirus RNA by Glimaker et al. 1993 (Glimaker et al., Detection of enteroviral RNA by polymerase chain reaction in the cerebrospinal fluid from patients with aseptic meningitis. Scand. J. lnf. Dis., 1993; 25: 547-57) was applied on the muscle biopsies, using the guanidine method of RNA extraction.

RESULTS and CONCLUSION : in spite of using different methods and different sample materials we were not able to identify any enterovirus parts or immune response to it.

ENTEROVIRAL REPLICATION AND CHRONIC FATIGUE SYNDROME - J.W. GOW, W.M.H. BEHAN, P. CASH, K. SIMPSON, D. KAY, M.M. MCGILL, P.O. BEHAN

Department of Pathology & Neurology, University of Glasgow, Southern General Hospital, Glasgow,
Medical Microbiology Department, Aberdeen University, Aberdeen, United Kingdom,

OBJECTIVES: it has been suggested that enterovirus persists in the muscle of patients with chronic fatigue syndrome (CFS) and that this may be due to a defect in a transcription giving rise to abnormal levels of genomic and template viral RNA strands. An in vitro model of a persistent coxsackie virus in human skeletal muscle cells and an in vivo infection in human muscle was therefore investigated for evidence of an alteration in the ratio of these strands.

METHODS : in situ hybridisation and a parallel complementary reverse transcriptase-polymerase chain reaction (RT-PCR) using three primer sets was employed to determine the amounts of genomic (coding) and template (non- coding) RNA strands. RNA was isolated from the patients' muscle biopsies and from the in vitro "carrier-culture" persistent enterovirus model. The latter consists of human skeletal muscle (rhabdomyosarcoma, RD) cells infected with a persistent coxsackie B3 virus (piRD-3673). RD and Hep2 cells infected with wild-type coxsackie B3 virus were used as positive controls and uninfected cells as negative controls.

RESULTS : in situ hybridisation and RT-PCR results demonstrated the normal ratio (approximately 1 00: 1) of genomic to template RNA strands in both the cell cultures and the muscle biopsies from patients with CFS.

CONCLUSION : these data support the hypothesis that persistent enterovirus infection is not dependent on abnormal transcription either in vitro or in vivo.
 
 

IMMUNOPATHOGENESIS OF CHRONIC FATIGUE SYNDROME - N. KLIMAS

Miami Veterans Medical Center and the University of Miami School of Medicine, Miami, Florida, USA

Chronic Fatigue Syndrome is characterized by a state of chronic immune activation and immune dysfunction, an observation confirmed by investigators in the U.S., Australia, Italy, Germany and the U.K. The Miami group has longitudinal data suggesting patterns of immune dysfunction that correlate with the relapse and remit nature of the illness. Specific patterns of solublemediators suggest a key role for tumor necrosis factor (TNF alpha), and TNF receptor. Miami and other groups have shown that the degree of cellular dysfunction correlate with illness severity.

Miami has also shown an increased relative risk for HLA DR3, HDL DR4, and HL DQ3 in the CFS population. Studies of perpetuating factors such as neuroendocrine dysregulation lead to the following model of the pathogenesis of CFS :

Genetic predisposition
Immune activation or suppressing infection or event Immune dysregulation
and chronic immune activation
Perpetuating factors
Health Outcome (Chronic Fatigue Syndrome)

IMMUNOLOGIC ABNORMALITIES IN CHRONIC FATIGUE SYNDROME - U. TIRELLI (1), M. TAVIO (1), A. PINT0 (2)

1 Division of Medical Oncology and AIDS, Centro di Riferimento Oncologico (CRO), Aviano, Italy
2 Leukemia Unit, Centro di Riferimento Oncologlco (CRO), Aviano, Italy

Chronic Fatigue Syndrome (CFS) is a recently defined illness of unknown etiology, characterized by unexplained, disabling fatigue lasting more than six months, chronic and recurrent low-grade fever, adenopathy, pharyngitis, and neuropsychological symptoms such as difficulties with concentration and depression. The centers for Disease Control and Prevention (CDC) have produced a working case definition for such an heterogeneous disease which relies on clinical and laboratory criteria. CFS has been mainly described in the U.S., Australia, and Great Britain, but also in Canada, New Zealand, Israel, Spain, France and Italy. A viral etiology for CFS has been suspected owing to the overlapping clinical features with post-viral fatigue, and a number of different viruses including Epstein-Barr virus , Human herpes virus-6 (HHV 6), enteroviruses, HTLV ll-related retroviruses, and spumaviruses, have been implicated in the development of CFS. Some immunological findings have in fact suggested infection by viruses or some other infectious organisms.

Immunological abnormalities so far associated with CFS include a decreased number and function of NK cells, the presence of chronically activated circulating T cells, abnormal distribution of T cell subsets, monocyte alterations, changes in B cells subsets, and abnormalities in cytokine serum levels or in vitro response of lymphocytes to mitogenic stimulatio.

Despite the large number of immunological abnormalities that have been found in patients with CFS, their significance is uncertain in that many variables have not been often taken into consideration. In particular: 1) immunological data have been evaluated at different stages of CFS, i.e. patients had different duration of their disease at the time of immunological evaluation; 2) specific methodologic problems have not been taken into consideration as far as the performance of cellular immune assays, for example there is a lack of interassay controls; 3) different techniques have been employed for the flow cytometric phenotyping of CFS patients, i.e. whole blood lysis methods vs. mononuclear cell separation or use of fresh vs. cryopreserved cells, which may account at least in part for the reported discrepancies among immunophenotyping studies; 4) most of the immunological abnormalities described did occuronly in a minority of patients with CFS; 5) the degree of immunological abnormalities do not correlate with the severity of symptoms; 6) very few or no opportunistic infections have been reported. Finally a relative low number of patients with a strictly-defined CDC diagnosis of CFS have undergone an extensive immunologic survey on the different series reported.

However, the main reason of differences in immunological abnormalities observed in patients with CFS might be due to the fact that current CFS definition may include different diseases with different etiopathogenesis processes. In particular there seems to be at least two groups of patients, one with clinical and immunological characteristics suggesting persistent fatigue following a viral illness and the second group of patients without a clear-cut viral onset and probably with some allergic or neurological disturbances as key defects. These variables affecting the interpretation and significance of immunological parameters will be addressed only by means of an international project with a standardization of both patients and techniques employed for the immunological analysis.

Finally, no single immunologic disturbance has been identified yet as typical of CFS. Overall, CFS appears most likely to be a chronic disorder of the immune system probably caused by an infectious agent, not necessarily a specific agent, with a chronic immune activation, in particular of cytokines and T lymphocytes.

CHRONIC FATIGUE SYNDROME: EVALUATION OF A 30-CRITERIA-SCORE AND CORRELATION WITH IMMUNE ACTIVATION - A. HILGERS, J. FRANK

Institut for angewandte Immunologie und Umweitmedizin, Duesseldorf, Germany

505 patients with no other definitive diagnosis and suspicion of chronic fatigue syndrome were checked by an 45-criteria-score. 15 criteria corresponded with the criteria of the Centers of Disease Control and were fulfilled by 385 patients. These 385 patients showed significant difference to 53 healthy controls in 40 of the 45 criteria (p < 0.001, twitches and food allergies p < 0.05). Furthermore sensitivity, specificity and precision of every criterion was calculated. The 15 CDC criteria were all significant (p < 0.001), 15 other significant criteria of descending precision were added : respiratory infections, palpitations, dizziness, dyspepsia, dryness of mouthleyes, allergies, nausea, paresthesia, loss of hair, skin alterations, lack of coordination, chest pain, personality changes, eczema, general infections, twitches, urogenital infections (precision of the 30 criteria: 95.7% down to 36.3%). Correlation (Spearman rank-correlation-coefficient rs ties corrected) between this 30-criteria- score and immunological parameters could be evaluated in 472 of the 505 patients. Significant positive correlation to the 30-criteria-score was found in: CD8+-T-Iymphocytes (rs = 0.083, p = 0.036),DR+-T-Iympho-cytes (rs, = 0.085, p = 0.032), gamma globulin (rs = 0.099, p = 0.016), IgM (rs= 0.145, p = 0.001), IgG (rs = 0.087, p = 0.029), and the number of types of autoantibodies (mainly ANA, ACA, thyreoidal and parital antibodies) (rs = 0.1274, p = 0.003); significant negative correlation was found in albumin-globulin-ratio (rs = -0.102, p = 0.014), eosinophils (rs = -0.106, p = 0.011) and IgE (rs, = -0.126, P = 0.020). Most of these parameters did also correlate with one another.

On the other hand in the group of the 505 patients serological tests of the following pathogens were striking: HHV-6-IgG in 243 of 487 patients (49.9 %), EBV-EA in 170 of 480 (35.4 %), HSV-KBR in 135 of 462 (29.2 %), CMV-KBR in 49 of 390 (12.5 %), Chlamydia-IgA in 142 of 406 (35.0 %). Borrelia western blot showed 3 or more specific IgG-bands in 54 of 131 patients (41.2 %). In single special cases infection with EBV, HHV-6 and CMV, respectively, was confirmed by DNA-PCR-test.

CONCLUSIONS : In more and more larger groups of patients with CFS and related disorders we often see clinical signs and longer history of other symptoms beside the classical criteria of CFS, specially a high prevalence of local and general susceptibility to infections and prolonged inflammatory processes. Together with other results published by us and other investigators the data further confirm the hypothesis that a reduced or unstable immune control or delayed immune reaction to persisting viruses or bacterial intracellular pathogens can - triggered by common infections or other environmental factors - lead to a chronic neuro-immune activation state and auto-immune disorders. Hypersensitivity symptoms of the patients might not be mediated by classical allergy with IgE and eosinophils.

LYMPHOCYTE SUBSETS, APOPTOSIS AND CYTOKINES IN PATIENTS WITH THE CHRONIC FATIGUE SYNDROME - C.M.A. SWANINK, J.H.M.M. VERCOULEN, J.M.D. GALAMA, M.T.L. ROOS, L. MEYAARD, J. VAN DER VEN-JONGEKRIJG, R. DE NIJS, G. BLEIJENBERG, J.F.M. FENNIS, F. MIEDEMA, J.W.M. VAN DER MEER

University Hospital Nijmegen, Departments of General Internal Medicine, Medical Microbiology, and Medical Psychology, and Central laboratory of The Netherlands Red Cross Blood Transfusion Service, laboratory for Clinical and Experimental Immunology, The Netherlands

Aim of this study was to investigate whether previously reported immunologic abnormalities could be reproduced in a randomly chosen group of patients with chronic fatigue syndrome (CFS), when compared to well-matched controls. An additional goal was to correlate immunologic abnormalities with fatigue severity, functional impairment, and psychological well-being. We performed immunophenotypic analysis of peripheral blood mononuclear cells (PBMC) from 76 patients with CFS and 69 simultaneously studied healthy controls, matched for gender, age, and neighbourhood. Furthermore, we measured circulating cytokines as well as the ex-vivo production of pro-inflammatory cytokines, using a whole blood culture system. Expression of CD11b on CD8+ cells was significantly decreased in CFS. However, the previously reported increased expression of CD38 and HLA-DR was not confirmed. There was no obvious difference in apoptosis in leucocyte cultures, circulating cytokines, and ex-vivo production of IL-la and IL-1 receptor antagonist. Endotoxin-stimulated ex-vivo production of TNF-a and IL-1b was significantiy lower in CFS. The immunologic test results did not correlate with fatigue severity or psychological well-being as measured by Checklist Individual Strength, Beck Depression Inventory and Sickness Impact Profile. Thus, these immunologic tests cannot be used as diagnostic tools in the individual CFS patient.
 
 

RADIONUCLIDE BRAIING IN PATIENTS WITH MYALGIC ENCEPHALOMYELITIS AND CHRONIC FATIGUE SYNDROME (ME/CFS) -D.C. COSTA

The Institute of Nuclear Medicine, UCL Medical School, London, United Kingdom

The increasing research on patients with Chronic Fatigue Syndrome and Myaigic Encephalomyeiitis has made more people aware of the heterogeneous character of this syndrome. Symptoms and signs presented by patients may be attributed to pathology in several systems rather than a particular organ. However, the majority of abnormalities reported by patients could be explained if pathology in the Central Nervous System was identified.

Several studies with radionuclides, particularly investigating the regional brain perfusion or cerebral blood flow, have demonstrated multiple areas of reduced cortical perfusion. The majority of the studies have used single photon emission tomography (SPET) and few position emission tomography (PET) techniques. We studied patients with Myalgic Encephalo-myelitis/ Chronic Fatigue Syndrome (ME/CFS) and compared their brain perfusion with that of normal volunteers and other patients with Major Depression. The results indicate that in addition to scattered cortical perfusion abnormalities, brain stem hypoperfusion (compared to normals) appears to be characteristic of ME/CFS patients, and significantly lower than depressed patients. The hypoperfusion to the brain stem was the lowest in those ME/CFS patients who fulfilled the CDC criteria and had no other psychiatric disorder.

In my opinion the potential value of brain radionuclide techniques with increasing number of more specific radiotracers to study neurotransmission should be explored in order to better understand the biological components of this syndrome. Last, but not the least, changes due to therapeutic trials could be better evaluated by using this radionuclide methodology.

MAGNETIC RESONANCE IMAGING AND TC-99M HMPAO SPECT IN 30 PATIENTS SUFFERING FROM THE CHRONIC FATIGUE SYNDROME - M. TROCH, L. LAMBRECHT, K. OSMANAGAOGLU, C. VAN DE WIELE, M. SIMONS, R.A. DIERCKX

Outpatient Internal Medicine Clinic, University Hospital Gent, Heilige Familie Hospital, Belgium

The diagnosis of CFS is based on the Centers of Disease Criteria, which also exclude any other underlying medical condition. At present, only limited data are available on the relative contribution of SPECT-scan as compared to MRI, yielding information respectively on functional and anatomical changes of the brain.

With this regard, a retrospective study was performed in 30 patients -out of a group of 183 ambulatory patients (1990 - 1995) - in whom both brain MRI and SPECT were performed. Ten men and twenty women, aged between 17 - 57 years (mean 35.4 yrs) were included. The mean interval between both examinations was 67 pm 47 days. SPECT was performed using a dual-head camera, equipped with LEHR collimators, 30 min after IV injection of 925 MBq Tc-99m HMPAO. Qualitative analysis of SPECT data was supported by semiquantitative criteria as suggested in literature. MRI, performed using a 1.5 Tesia magnetron equipment, was done during the clinical working-up if considered potentially helpful. Protondensity, T1- and T2- weighted images were acquired. Both MRI and SPECT were evaluated by 2 experienced observers, with regard to the number and location of focal abnormalities. Both MRI and SPECT scans were normal in 19 patients. In 3 patients with normal SPECT findings, MRI showed a solitary focus of demyelinisation, respectively: hippocampal, in the corona radiata and right frontally, whereas SPECT findings were normal. In 6 patients MRI was normal, where as SPECT of the brain showed regions of hypoperfusion in the left hemisphere in 5 patients, respectively : temporolaterally (number of patients, n = 2), temporomedially (n = 1), temporooccipitally (n = 1), frontoparietally (n = 1) and parietally (n = 1). The 6th patient showed multiple regions of hypoperfusions in the whole right hemisphere, preponderant temporally. In 2 patients, in whom both MRI and SPECT were abnormal, findings were discordant with regard to the localization of the lesions.

Similar to the only report (Schwartz et al., 1994) comparing SPECT and MRI in CFS patients, SPECT findings occurred more frequently and with higher numbers of lesions in the whole population, as compared to MRI. Interestingly, in 7 of 8 patients showing abnormal SPECT findings, the latter were also preponderant in the left cerebral hemisphere, especially temporally.

In conclusion, although the incidence of both SPECT and MRI abnormalities in this series may be considered low, SPECT abnormalities are more frequent and occur in higher number as compared to MRI. Hypothetically, the predominance of SPECT abnormalities in the left temporal lobe may be associated with the selective verbal memory deficits described in patients suffering from CFS.

POLYSOMNOGRAPHY AND TC-99M HMPAO SPECT IN 21 AMBULATORY PATIENTS SUFFERING FROM THE CHRONIC FATIGUE SYNDROME -C.VAN DE W IELE, L. LAMBRECHT, M. TROCH, K. OSMANAGAOGLU, G. HOFFMANN, O.LEBON, R.A. DIERCKX

Heilige Famille Hospital, Gent, University Hospital of Gent, Outpatient Internal Medicine Clinic, University Hospital Brugmann, Belgium

Most patients suffering from CFS present with sleep disorders, which are likely to contribute to daytime fatigue. Moreover, the severity of the sleep disorder as measured by polysomnography is proportional to the clinical functional impairment (Morriss et al., 1993). A correlation between polysomnography and SPECT may be expected, since several authors have reported : (1) the usefulness of Tc-99m HMPAO brain SPECT for demonstrating functional impairment of the brain in CFS patients and (2) the correlation of SPECT abnormalities with the patient's performance status.

Hence, a retrospective study (1990 - 1995) was performed in 21 ambulatory patients, fulfilling the Centers of Disease Criteria for CFS and in whom both polysomnography and SPECT were performed. Sixteen women and five men, aged between 22 - 54 years (mean 35.4 yrs) were included. The mean time interval between both examinations was 17 pm 7 weeks, during which time the clinical status as judged by the Karnofsky performance scale remained unaltered. SPECT was performed using a dual-head camera, equipped with LEHR collimators, 30 min after IV injection of 925 MBq Tc-99m HMPAO. Qualitative analysis of SPECT slices by 2 experienced nuclear physicians was supported by semiquantitative criteria, as suggested in literature. Polysomnography, performed using sleep analysers with 17" monitors (Nicolet Ultrasom) and subsequently corrected epoch per epoch (30 sec) by one of the authors (G.H.) using Rechtschaffen and Kales criteria, was evaluated by 2 experienced neurologists. The recorded data were compared to the results obtained in 20 age-matched, healthy volunteers. Subsequently, the number of SPECT lesions was correlated with the variables measured by polysomnography.

In 3 patients, SPECT of the brain showed focal left temporolateral hypoperfusion, whereas in the remaining 18 patients, SPECT scan findings were normal. Using a u-test, the following polysomnographic variables were found to be significantly different in the group of 21 patients as compared to the controls: total time asleep, time taken to fall asleep, time awake after the start of sleep, sleep efficiency, duration of rapid eye movement sleep. No statistically significant correlation between the number of SPECT abnormalities and any of the variables measured by polysomnography was found.

In conclusion the presented series suggests the absence of a correlation between polysomnographic data and SPECT scan findings in ambulatory patients suffering from Chronic Fatigue Syndrome.
 
 

GENERALISED ANXIETY DISORDER IN THE CHRONIC FATIGUE SYNDROME - B. FISCHLER, R. CLUYDTS, V. DE GUCHT, L. KAUFMAN, K. DE MEIRLEIR

Departments of Psychiatry (Academic Hospital A.Z. V.U.B.), Psychology, Medical Statistics/Biostatistics and Sports Medicine, Free University of Brussels (Vrije Universitelt Brussel, Belgium

Significantly higher prevalence of major depression (MD) in CFS as compared with chronic medical conditions were reported in several controlled studies. Etiopathogenic or physiopathological links between MD and CFS were hypothesised.

A structured psychiatric interview including a global psychopathological approach as well as an assessment of fibromyaigia (FM) comorbidity are performed in a group of consecutive CFS patients.

A higher rate of current anxiety disorders (75.5 %) is found than current mood disorders (30.2 %). We do not find a higher prevalence of current MD in CFS as compared with reported rates in chronic medical conditions. A very high rate (56.6 %) of early onset, trait-like, ego-syntonic, psychiatric comorbid GAD is demonstrated. Possible links between anxiety and fatigue are suggested. However, GAD patients do not have distinct illness or sociodemographic features compared with other CFS patients. The prevalence and distribution of psychiatric disorders is the same in CFS patients with or without FM.

ANALYSIS OF ASPECTS OF PERSONALITY AND LIFE STYLE IN CHRONIC FATIGUE SYNDROME - E. NEERINCKX (1), B. VAN HOUDENHOVE (1), H. BOBBAERS (2), D. BLOCKMANS (2), P. ONGHENA (3), D. SCORETZ (4)

1 Psychosomatic Rehabilitation Unit, Catholic Universitelt leuven, Belgium
2 General Internal Medicinen Catholic University leuven, Belgium
3 Faculty of Psychology, Catholic University leuven, Belgium 4 Faculty of Physical Education and Physiotherapy, Catholic         University Leuven, Belgium

OBJECTIVES : to determine the interference of personality characteristics, premorbid life style and stress in patients with chronic fatigue.

METHODS : fortyfour patients (33 females/11 males) consecutively recruited for the study, completed questionnaires on premorbid action-proneness (Habituele Actie-Bereidheidsschaal, 1970), anxiety (STAI, 1970), daily hassiess (Alledaagse ProblemenLijst, 1994) and personality characteristics (Personality Diagnostic Questionnaire Revised, 1992).

RESULTS : patients report high levels of stress in their lives, in the months preceding the first consultation, as well as levels of trait and state anxiety that are above normal. In addition, diverse personality disturbances are prominent. Finally the investigation confirms previous reports that CFS patients lead hyperactive or "action-prone" premorbid lifestyles. Regression models reveal that anxiety, stress and age play a role in the high levels of mental commitment and physical involvement reported by these patients.

CONCLUSION : the results of this study fit with the hypothesis that "being active" may be a crucial factor in the life of these patients. Clinical observations suggest that this activity could be a coping strategy to deal with emotional stress and that fatigue may be considered as the symptom of the fighter getting exhausted. Further research should clarify this line of thought.
 
 

CHRONIC DEBILITATING FATIGUE: PERSPECTIVES IN IRISH GENERAL PRACTICE - E. J. FITZGIBBON, D. MURPHY, K. O'SHEA, C. KELLEHER

Irish College of General Practitioners with the Department of Health Promotion, University College Galway, Ireland

Fatigue is a common complaint in the general practice setting. Some 10 - 30 % of routine attenders are affected. Most of these are given psychiatric diagnoses, and a very small percentage are eventually given a physical diagnosis, but there is an irreducible minority of patients whose fatigue cannot be explained by physical of psychiatric paradigms. This phenomenon has led to various working case definitions for a Chronic Fatigue Syndrome.

OBJECTIVES : of this study are (i) to estimate the perceived incidence of chronic debilitating fatigue of unexplained origin in Irish General Practice, (ii) to explore the attitudes of Irish general practitioners towards the concept of a distinct chronic fatigue syndrome, and (iii) to obtain information on the management and outcome of affected patients.

METHODS : 200 general practitioners were chosen at random by computer. Each was sent a questionnaire with a covering letter. Chronic debilitating fatigue was defined as a fatigue of at least 6 months duration which could not be explained by physical or psychiatric means. Respondents were asked to include patients whose fatigue started immediately after a viral infection, and to also include patients who continued to complain of debilitating fatigue after adequate treatment for presumed psychiatric disorders. Information was sought on : a) practice size, age and sex of doctor, and whether the doctor recognised patients with chronic debilitating fatigue within the practice list, b) the attitudes of respondents toward the management of such patients and the quality of care they receive, c) initials, date of birth, sex, and occupation of patients with Chronic debilitating fatigue, d) attitudes of respondents towards a distinct chronic fatigue syndrome (e.g., do you ever consider the diagnosis of CFS, are you confident in making a diagnosis of CFS, do you accept the existence of a CFS, etc).

CONCLUSIONS : data is now being collated from this study and will be presented in poster form.

SYMPTOM PERCEPTIONS AND QUALITY OF LIFE IN PATIENTS WITH CHRONIC FATIGUE SYNDROME (CFS) AND GI DISORDERS - H.HYMAN, T. WASSER

Lehigh Valley Hospital, Allentown, Pennsylvania, U.S.A.

OBJECTIVES : the relationship between GL symptomology with CFS has been cited by Diehi et al. Our study was conducted to examine the overall differences in symptoms and quality of life among patients presenting to a GI service with various combinations of CFS and GI complaints.

METHODS : using existing medical records from a private GI practice three groups of patients were identified and selected for this analysis. These three groups were prospectively surveyed using both the Medical Outcomes, Study Short Form 36 (SF-36) and the Symptom Index Survey (SIS) a broad ranging questionnaire sampling 19 categories of general physical symptoms. Group one consisted of patients positively diagnosed with CFS and a GI disorder (n = 5).Group two consisted of patients reporting to the GI practice with GI symptoms butwithout a subsequent GI diagnosis, and positively diagnosed with CFS (n = 6). Group three consisted of patients positively diagnosed with a GI disorder without CFS (n = 11). Analysis of Variance (ANOVA) techniques were applied to the data across both questionnaires, post-hoc comparisons were made using the Scheffe procedure, unless otherwise noted. An overall alpha level of ( a 0.05) was considered significant for each ANOVA procedure.

RESULTS : the data indicate that CFS patients in both groups one and two report many more problems with general symptoms than non-CFS patients (group 3)as measured by the SIS. Among these differences : Allergies (p = 0.0115,group 1 from 3), Digestive Tract (p = 0.0243, group 1 from 3), Ears (p0.0305, group 1 from 3), Eyes (p = 0.0006, group 1 and 2 from 3), Head (p0.0022, group 1 from 3), Joints/Muscles (p = 0.0364, group 1 from 3, Tukey post-hoc), Lungs (p = 0.0340, group 2 from 3, Tukey post-hoc), and Metabolism/ Endocrine (p = 0.0140, group 1 from 3).

The SF-36 also revealed the same statistical patterns (CFS patients experiencing more problems than GI patients) among all eight sub-scales, two of which reached statistical significance. General Health perception was lower (p = 0.0237, group 1 from 3), as was Energy/Fatigue (p = 0.0335, group 1 from 3) in the CFS and GI group.

CONCLUSIONS: the fact that CFS patients tend to present with GI complaints may demonstrate the relationship between these two diagnoses. While this series is not large, this relationship seems to be increasing in incidence. That the observed differences occur mainly between groups 1 and 3, both with working GI diagnosis codes, indicates that these differences are a result of the presence or absence of CFS.

CHRONIC CIGUATERA: ONE ORGANIC CAUSE OF THE CHRONIC FATIGUE SYNDROME - J. PEARN

Dept. of Child Health, Royal Children's Hospital, Australia

Post-acute ciguatera is one organic cause of Chronic Fatigue Syndrome; and as such forms one important model of this condition which can be studied prospectively. A minimum of 10 % of sufferers of acute ciguatera progress to the chronic state; and of these, a significant proportion experience symptoms of lassitude, joint pains and easy fatiguability over the ensuing months and years. Case studies of Mannitol treatment in the acute post- intoxication phase indicate that the duration of chronic symptoms can be shortened. The implication of the ciguatera case studies is that there may be other food-chain toxins which can cause the Chronic Fatigue Syndrome.

Ciguatera affects thousands of individuals of the ]ndo-Pacific and Caribbean regions annually; and with the convenience and safety of air freight, occasional cases of ciguatoxic fish poisoning occur in Europe.