POSTER SESSION I

PERSISTENT PARVOVIRUS B 19 INFECTION; AN ASSOCIATION WITH CHRONIC FATIGUE SYNDROME - J.R. KERR (1), M.D. CURRAN (2), J.E. MOORE (1). A.M. BARRETT (3), D. MIDDLETON (2) E. DERMOTT (3)

1 Dept. of Bacteriology, Belfast City Hospital, Northern Ireland
2 Dept. of Tissue Typing, Belfast City Hospital, Northern Ireland
3 Dept. of Microbiology and lmmunobiology, Queen's University of Belfast, Northern Ireland

Fifty-three patients with acute B19 infection were studied; symptoms at acute infection were rash and arthraigia (n = 26), rash (n = 7), arthraigia (n = 16), aplastic crisis (n = 3), and intrauterine fetal death (n = 1). These patients were followed for 26-85 months (mean 57 months) and re-assessed for persistent symptoms, anti-B19 antibodies, and B19 DNA. At follow-up, 7 individuals were positive for serum B19 DNA, compared with none of the controls (2-tailed P value = 0.016). 2 patients had arthralgia and chronic fatigue syndrome (CFS) at follow-up; a 22 year old girl and a 49 year old man. For the 7 persistently infected patients, serum from the time of diagnosis of acute B19 infection was available for four, all of which contained B19 DNA. With single-stranded conformational polymorphism (SSCP) assay of these 11 PCR products, identical SSCP types were demonstrated in 5 of 7 follow-up isolates.

In 2 of the 4 cases for for which both acute and follow-up PCR product was available, the SSCP type of the follow-up product was different from that of the acute product. Two B19 virus types were demonstrated in the 22 year old girl with persistent arthraigia and chronic fatigue syndrome at follow-up.

MITOCHONDRIAL DELETIONS IN CHRONIC FATIGUE SYNDROME - W.M.H. BEHAN. J.W. GOW, K. SIMPSON, D. KAY, M.M. McGill, P.O. BEHAN

Department of Pathology &.Neurology, University of Glasgow, Institute of Neurological Sciences, Southern General Hospital, Scotland, UK

OBJECTIVES : it has previously been suggested that abnormalities in mitochondrial structure and function may play a role in the chronic fatigue syndrome (CFS). Such abnormalities are likely to reflect changes in the mitochondrial genome. Alterations in the genome itself depend on a number of factors, e.g. genetic, environmental and ageing. We examined muscle and nervous tissue samples from patients with CFS for the common mitochondrial deletions 4977 bp and 7436 bp.

METHODS : muscle biopsy samples from 8 patients with CFS, 22 'with an inflammatory myopathy (polymyositis/dermatomyositis) and 22 with other neuromuscular diseases, were examined for the mtDNA4977 and mtDNA7436 deletions, using the polymerase chain reaction (PCR) and Southern blot analysis followed by densitometry. Samples from the hypothalamus of a patient with CFS who had died was similarly compared to three central nervous system samples from patients dying of unrelated causes. All subjects were less than 40 years old since it is known that the incidence of these deletions increases significantly beyond this age.

RESULTS : two of the eight muscle biopsy samples from patients with CFS were positive for the mtDNA4977 bp deletion, compared to 4 of 22 in each of the other muscle biopsy groups. Densitometry showed that in one of the CFS samples, 21 % of the total mtDNA was deleted. The brain sample from the case of CFS was also positive for the mtDNA4977 deletion; the three controls were negative. None of the samples from any of the groups was positive for the mtDNA bp 7436 deletion.

CONCLUSION : a small proportion of patients with CFS has deletion of mtDNA4977. It is possible that this plays a role in the affected cases.

LOW SERUM b2- MICROGLOBULIN LEVELS IN CFS PATIENTS -- P.DE BECKER (1). K.DE MEIRLEIR (1), C. DEMANET (2), L. WETS (1), E. JOOS (1), J. SMITZ (3)

1 Human Physiology, HILOK, Vrije Unlversitelt Brussel, Brussels, Belgium
2 Department of Haematology and Immunology, A.Z. V.U.B., Brussels, Belgium
3 RIA laboratory, A.Z. V.U.B., Brussels, Belgium

OBJECTIVE : elevations of serum b2-microgiobulin (b2m) have been described in patients with a variety of illnesses, including malignancies, acquired immune deficiency syndrome and rheumatic disease. b2m is a low molecular weight polypeptide synthesized by all nucleated cells of the body. It forms part of the HLA class I antigens on the cell membrane. Because abnormalities of both humoral and cellular immunity have been demonstrated in a substantial proportion of patients with CFS measured serum b2m and compared it to those of matched controls.

METHODS : from our outpatient clinic we recruited 18 patients (mean age SD; 34.8 pm 6.49) who met the CDC criteria for CFS. All patients had been investigated to exclude alternative medical diagnosis. Controls were 14 age- and sex- matched healthy individuals (mean age pm SD; 34.7 pm 7.25); all were free of major medical or psychiatric diseases. Data were analyzed by using Student's t-test; a p value < 0,01 was considered statistically significant.

RESULTS : mean b2-microglobulin levels of CFS-patients pm SD = 0,981 UG/L pm 0,123; mean b2-microgiobulin levels of matched controls pm SD = 1,179 0,246 (p = 0,0012).

CONCLUSION : our data show that CFS patients have lower serum b2- microglobulin levels compared to controls. Although this is not a diagnostic marker, it adds to the numerous disturbances observed in the immunity of CFS patients.

IMMUNOPHENOTYPING BEFORE/AFTER AMPLIGEN -TREATMENT IN CFS - PATIENTS -K.DE MEIRLEIR (1), P. DE BECKER (1), E. JOOS (1), l. WETS (1), C. DEMANET (2), L. DE HAUWERE (1), B. FISCHLER (3), J. DE GREVE (4)

1 Department of Human Physiology, HILOK, Vrije Universiteit Brussel, Brussels, Belgium
2 Department of Haematology and Immunology, A.Z. V.U.B., Brussels, Belgium
3 Department of Psychiatry, A.Z. V.U,B., Bruu&s, Belgium
4 Department of Oncology, A.Z. V.U.B., Brussels, Belgium

Ampligen has been used in a number of studies in the treatment of CFS- patients. Patients showed clinical improvements, as well as cognitive improvement.

METHODS: We compared immunophenotypes of CFS-patients (n='32). Two groups of patients were examined : group A consisted of CFS-patients who received Ampligen I.V. twice a week for a period of 24-36 weeks. The immunophenotypes were obtained before and after the treatment period. Group B were CFS-patients who did not get any treatment (nor any other intervention); they continued on doing their normal activities. Immunophenotypes were taken with an intervalperiod that was similar to the treatment period. Following parameters were obtained (both relative values as well as absolute values): CD2+, CD3+, CD3+ HLADR+, CD2+ CD25+, CD4+, CD4+CD4SRA-, CD4+CD45RA-, CD4+ Leu8-, CDB+, CD8+ CDllb+, CD8+CD11b-, CD8+CD57+, CD19+CD20-, CD3- CD16CD56+, CD3+CD16CD56+.

RESULTS : Group A : A significant decrease post-treatment was observed in following markers: CD2+ (%), CD8+ CD11b+ (%, ABS), CD8+CD57+(%, ABS). A significant increase post-treatment was observed in CD8+ CD11 b- (%, ABS). Group B : No significant differences were found.

CONCLUSION : Along with significant clinical improvements which we observed in our Ampligen treated patients an increase in CD8+, CD11b- was observed. As a decrease in CD8+ CD11b- positive cells is observed systematically (Jay Levy et al.) in CFS patients, the Ampligen induced change might be an indicator of a therapeutic effect of this drug.

PRELIMINARY EVIDENCE FOR AN ASSOCIATION BETWEEN CHLORINATED HYDROCARBONS AND CHRONIC FATIGUE SYNDROME - R.H. DUNSTAN (1), M. DON0HOE (3), W. TAYLOR (1), T.K. ROBERTS (1), R.N. MURDOCH (1), J.A. WATKINS (1), N.R. MCGREGOR (2)

1 Dept. of Biological Sciences, The University of Newcastle, Callaghan, Australia
2 Neurobiology Research Unit, Centre for Oral Health Research, University of Sydney, Westmead Hospital, Australia
3 Environmental Medical Centre, Mosman, Sydney, Australia

Pesticides have been associated with fatigue symptoms and are presently an exclusionary criteria for chronic fatigue syndrome (CFS) (Centres for Disease Control, Atlanta, USA).

We studied the serum levels of chlorinated hydrocarbon pesticides in CDC (1988) defined CFS patients (n = 39) and healthy age- and sex-matched controls (n = 34). Twenty-one patients met the CDC definition and did not report toxic chemical exposure, whilst seventeen patients who met the CDC criteria reported a history of toxic chemical exposure (Toxic exposure group). The pesticide levels in the three groups were compared.

DDE [1,1-dichioro-2,2-bis (p-chlorophenyl) ethene] was detected in all serum samples at levels greater than 0.4 pbb. The incidence of HCB (hexachiorobenzene) contamination (at levels > 2.0 ppb) was higher in the CFS group (45 %) compared with the non-CFS control group (21 %, p < 0.05). The CFS group had a higher total organochiorine level than the control group (p < 0.05). The toxic exposure group also had a higher mean organochlorine level than the control group, but the difference was not significant. DDE and HCB comprised more than 90 % of the total organochlorines measured in each of the sample groups. The levels of recalcitrant organochlorine levels measured in serum from CFS patients were higher than those in control subjects, suggesting that these chemicals may have an aetiological role in this cohort of CFS patients.

Exclusion of patients from the CDC CFS research definition on the basis of a reported history of known exposure to toxic chemicals is not valid as no differences in pesticide concentrations were found between those reporting and not reporting exposure. The role of low level organochlorine bioaccumulation in the development of CFS symptoms requires further investigation.
 

SOLUBLE RECEPTORS AND CHRONIC FATIGUE SYNDROME (CFS) - M.A. FLETCHER. R. PATARCA, N.G. KLIMAS

University of Miami School of Medicine, Miami, USA

Several research groups, including ours, have reported that 20 to 60 % of patients diagnosed with CFS have evidence of one or more immune function parameter abnormalities. These abnormalities include increased activation markers on lymphocytes, decreased cellular immune function and increased levels of certain cytokines and other soluble markers, such as neopterin and S-2-microgiobulin. In the present study, we focused on soluble tumor necrosis factor receptors (sTNF-RI and sTNF-RII), soluble interleukin-6 receptor (slL6-R) and soluble intercellular adhesion molecule -1 (slCAM-1). These receptors were determined on samples of serum using commercial sandwich type immunoassays.

We anaiyzed a total of 108 CFS patient's samples, which had been collected over a period of 5 years, with at least 2 and up to 8 time points per patient. A total of 190 healthy controls were studied. The sample included 19.5 % males. This made it possible to assess the relationship between gender and the immunologic variables under study. Levels of sTNF-RI, sTNF-Rll, slL-6R, and slCAM-1 were found to be consistently higher among males than females and among CFS patients as compared to controls.

The cellular source of the STNF-Rl and ll, as well as the other soluble receptors, in these patients is unknown, but worth pursuing as suchknowledge may aid in the search for an etiology of this complex syndrome.

This research was supported by an grant from the Chronic Fatigue and Immune Dysfunction Syndrome Foundation, Charlotte, North Carolina and by a donation from Mrs. Lottie Morton, Miami Beach, FL

FEATURES OF CHRONICITY IN ME/CFS: A CASE SERIES IN THE UK - R. GIBBONS, A. MACINTYRE. C. RICHARDS CHROME: Case History Researcn on ME, U.K,

OBJECTIVES : the objectives of the research were to identify the group of patients in the UK who have been rendered so chronically disabled by ME/CFS that they cannot leave home unassisted, and to assess aspects of their physical and cognitive levels of disability at the onset of the illness and at present.

METHODS : participants were sought through the patient organisations and through individual physicians, and data, in the form of detailed case histories, was collected by means of self-report questionnaires. All patients fulfilled the CDC criteria, and had received a diagnosis of ME/PVS/CFS from a general practitioner or a hospital consultant. The following further criteria were also applied: (i) chronicity (duration of illness of not less than two years) (ii) a specified level of disability (inability to leave home without assistance).

RESULTS : patients identified : 147 to date (and steadily accumulating); duration of illness : > 5 years 81 %, > 10 years 38 %; death : 2 (the first after a 15 year illness, the second after 7 years).

sample measures of disability at onset of illness at present

can get out of bed without difficulty 81/129 (63%) 51/131 (39%)
can get to toilet 78/130 (60%) 48/131 (37%)
can walk around house without difficulty 64/129 (50%) 19/130 (15%)
cannot recount contents of 30 min radio 37/128 (29%) 50/130 (38%)
standing impossible 43/128 (29%) 87/131 (66%)

CONCLUSION : these preliminary results suggest that, in a percentage of cases of ME/CFS, chronicity, of a scale not previously documented, is a significant feature of the disease. They also suggest that certain physical and cognitive disabilities increase with increasing chronicity.

PATTERNS OF IMMUNE DYSFUNCTION IN PATIENTS WITH CFS - L. HABETS, H. KNECHTEN, P. BRAUN

Praxenzentrum Blondelstr PZB, Aachen Germany

Immune dysfunction/dysregulation is the central finding in CFS even when aetiology is different. Besides the wellknown serological findings of IgGsubciass deficiency, and viral reactivation markers the impact of lymphocyte subclass determination and their activation states on diagnosis of CFS remains controversial as pathological findings were sometimes unequivocall and the relevance was doubted.

In 60 patients with clinical findings and complaints attributed to CFS the following lymphocyte subsets and their activation markers were measured on a Becton-Dickinson Facscan: CD3, Bcells CD1 9, helper CD3+, CD4+, Suppressor CD3+, CD8+, NK, CD16+, CD56+, activated CD8 (cytotoxic) CD8 HLA-DR+, CD8+-CD38+, CD8+-CD28+, CD8-CD11b+.

According to the major pathological mover (e.g. allergy, viral reactivation, environmental toxicity, M. Gilbert or mixture of these) distinct patterns of immune dysregulation were seen. In allergy driven CFS hyperproliferative extended but balanced subsets with differing activation signs were seen. When viral reactivation was dominant dysbalanced, highly activated subsets were found. Mostly however low suppressor cells with hypoactivation can be seen. In patients with signs of autoimmunity heavily dysbalanced overactivated immune situations are observed.

More comprehensive analysis of CD4 and CD8 subgroups and especially their activation states should lead to a better understanding of CFS immune- pathology and cristailyzation of those markers who are relevant for diagnosis and therapy control.

CLINICAL FEATURES OF THE CHRONIC FATIGUE SYNDROME - N. HASHIMOTO, D. KUROSAKA, T. YOKOYAMA, S. FUJITA, Y. OZAWA, I. NAKAYAMA, I. KINGETSU

Jikel Unlversity School of Mediclne, Tokyo, Japan

The features of CFS appeared to be an overlap of the clinical features of four conditions, i.e., an acute viral infection (e.g., upper respiratory infection like flu), a collagen disease, a somatoform disorder (e.g., somatization disorder), and a mood disorder (e.g., dysthymia).

A radar chart is made to give these symptoms placed evenly around the circumference of a circle. In clock-wise on the radar chart, area I (top right) represents the symptom profile for a viral infection, area II (bottom right) the profile for a collagen disease, area Ill (bottom left) the profile for a somatization disorder, and area IV (top left) the profile for a dysthymia. Each spoke of a radar chart implies a symptom and the severity of each is devided into 5 levels. The sum total of the area encompassed by the points plotted on the spokes is used to determine severity as the symptom score according to calculation.

Thus, if all symptoms are plotted at the midpoint of each spoke (2.5), the total area becomes 18.75, and this was determined to be the theoretical midpoint. A total area (symptom score) of 12-27, was classified as moderate, less than 11 was mild, and over 28, severe. A radar chart is then available for clarifying the clinical features and determining the severity of CFS. Because objective assessment is difficult in practice, using the radar charts to represent clinical symptoms is useful for assessing severity and for follow-up. Where dysthymia and somatization disorder elements are strong, the diagnosis of CFS should be made with caution.

TIREDNESS, CHRONIC FATIGUE AND CHRONIC FATIGUE SYNDROME AS CONTINUUM OF VITAMIN D-DEFICIENCY OR RELATED DISORDERS OF CALCIUM METABOLISM -- A.D. HOCK

Office of Internal Medicine and Psychotherapy, Koln, Germany

The method of this research study consisted of observing the psychosomatic signs of tired people of different severity and correlating them to different levels of vitamin D in Serum. It was by chance to detect that vitamin D-deficiency was the main cause of fatigue besides deficiency of iron or magnesium or more rarely derangements of thyroid function. Some tired patients showed hypoparathyroidism, mostly with normocalcemia instead of vitamin D deficiency. Severeness of fatigue correlated directly to the degree of psychosomatic disturbance and indirectly to vitamin D levels. Substitution of Vitamin D reversed fatigue and psychosomatic disease in modestly ill patients very quickly, in severe cases it was not possible to reverse complaints fully

The effect of vitamin D could be optimated by adding some magnesium and phosphate. Chronic fatigue patients seemed to respond partially, especially pains in muscle, joints and bones disappeared, but cyclic fatigue and high chemosensitivity persisted the 9 months of observation. The given doses of vitamin D ranged from 2.000 I.U. to 10.000 I.U. In cases of typical clinical signs, but without low vitamin D levels, remissions could be reached as well, proofing the suspicion of hidden vitamin D-deficiency or ineffective PTH. The high correlation of deficiency of vitamin D with iron deficiency was striking and gives idea of disturbed mineral and metal resorption.

The correlation with thyroid disease is a challenge to endocrinologists and immunologist.

AEROBIC TRAINING PROGRAMS IN CFS PATIENTS WITH FIBROMYALGIA: EFFICIENT ? -- E. JOOS, R. MEEUSEN, P. DE BECKER, P. DENDALE, K. DE MEIRLEIR

Dept. of Human Physiology, HILOK, Vrije Universitelt Brussel, Bruuds, Belgium

In earlier studies we found very low maximal. and submaximal work output in CFS patients. Resting heart rate was high [90 bpm (pm 14)] confirming the physical deconditioning. 27/100 patients did not even reach a RQ = 1 (VO 2 /VCO 2 = RQ), a parameter in defining the highest aerobic performing level in 73 other patients work output at RQ = 1 was 72 Watt (# 31 ) at a heart rate 135 bpm (# 22), this are very low values for aerobic capacity.

An individual rehabilitation program is made for some of these patients. They had to exercise every day, for 5 to 20 minutes at a heart rate = (heart rate at RQ = 1 # 5 bpm); constantly registered on a heart rate monitor. If RQ = 1 was not reached 70 % of maximal attained heart rate was used. They are followed every 4 weeks.

10 of these patients were tested on a bicycle ergometer at start and 4 to 12 months after starting the exercise program. 2 patients had lower maximal values, they were only exercising for 4 and 5 months; moreover patient nO 8 did not reach a maximal value at the second test and patient nO 7 performed better on submaximal values (70 -> 80 Watt at RQ = 1). After more than 6 months of training they performed better on maximal and submaximal values. This population is still too small to make conclusions, but we see a tendency toward good results.

There were 2 drop-outs until now, one due to another diagnosis (scieroderma) and another patient interrupted the treatment after 3 weeks. The results of 8 patients are listed in the table below.

WATT max HR max WattRO HR RQ Watt max' HR max' 1 160 179 100 117 190 168 2 120 193 70 166 130 191 3 130 188 80 138 130 177 4 110 149 130 139 5 80 134 60 111 130 150 6 60 141 80 140 7 110 162 70 137 90 135 8 70 130 130 120

Watt RQ' HR RQ' after 1 150 151 12 months 2 90 175 12 months 3 90 146 10 months 4 120 132 8 months 5 90 126 6 months 7 80 133 5 months 8 4 months

THE CHRONIC FATIGUE SYNDROME: A COST-BENEFIT ANALYSIS OF DIAGNOSTIC APPROACH - L. LAMBRECHT, M. TROCH, R.A. DIERCKX, C. VAN DE WIELE

Outpatient Internal Medicine Clinic, Hellige Familie Hospital and University of Gent, Belgium

In the absence of a diagnostic marker, objectivation of CFS may be difficult. In reviewing individual cases of patients, we concluded that the majority of procedures and hospitalisations could have been avoided had the attending physician(s) understood the symptoms and typical course of CFS.

Hence, the aim of this study was to assess the socioeconomic impact of prior diagnostic evaluation completing a survey concerning onset of illness as well as physician and alternative medical visits, any advanced medical test that was performed, and an estimate of money spent on diagnostic medical care prior to formal diagnosis at our center.

The study group consisted of 32 consecutive patients screened on a 6 month period, twenty-two women and 10 men, range 18-51 years (mean 29.1 yrs) showing Karnofsky performance scale scores (reflecting severity of performance disability) of 80-90 (number of patients, n = 12), of 70 - 80 (n = 12), and of 60 - 70 (n = 8).

The average period of illness before preliminary diagnosis at our center was 23.3 months (range 16 - 42 months). In that period of time, 641 visits were made to primary care physicians, or an average of 20 visits per patient, 322 visits were made to alternative medicine consultants, or an average of 10 visits per patient. Quack remedies (including therapy with ephedrine, corticosteroids, polypharmacologic thyroid extracts .... ) had been started in 7 out of 32 patients. Before the first visit at our center the patients underwent a total of 22 computer somographic and 5 magnetic resonance imaging brain scans, 28 other radiographic procedures, 6 endoscopies, 4 laparascopies, 16 electro-encephalographic and 12 electromyographic studies, 113 blood studies of more than 20 parameters and a total stay of 116 days of hospitalisation in an effort to treat their symptoms.

The cost of prior diagnostic investigations ranged from 600 to $ 52,000 per patient with an average of $ 20,500 per patient, excluding the cost of hospitalisation and of medical treatment(s). In comparison, the present average cost to exclude other causes of chronic fatigue and to establish a confident workdiagnosis of CFS in our center is about $ 1200, an amount we hope to reduce even more in view of our recent experience focused on combinating clinical evaluation with selective laboratory tests and individually planned brain SPECT-scan data.

In conclusion, early diagnosis of CFS may improve comfort for patients, while markedly reducing the costs of medical care.

HYPOTHALAMIC-PITUITARY-ADRENAL AXIS FUNCTION IN CHRONIC FATIGUE SYNDROME: A STUDY OF FAST FEEDBACK MECHANISMS - E.T. LAVELLE, T.G. DINAN

Dept. of Psychological Medicine, St Bartholomew's Hospital, London, United Kingdom

The Centre for Disease Control (CDC) definition of the Chronic Fatigue Syndrome has provided an objective basis for the diagnosis of this common syndrome. Numerous studies have been conducted in an effort to define the pathophysiology of the condition but although positive findings have been reported, very few of these have stood the test of replication. Recently Demitrack et al. (1993) reported significant abnormalities in the hypothalamic-pituitary-adrenal axis (HPA). These abnormalities included low production of cortisol and blunted CRH mediated ACTH release.

In an effort to further explore this phenomenon, we have examined fast feedback responses in patients with a CDC diagnosis of chronic fatigue syndrome. Patients presented at 0830h and had a cannula inserted in a forearm vein. Hydrocortisone was infused at a rate at 5 pg per kg per min for 90 minutes and the ACTH response was monitored. Those patients with a diagnosis of chronic fatigue syndrome responded with greater fails in ACTH than did healthy controls.

We hypothesise that supersensitivity of central glucocorticoid receptors may explain the low levels of cortisol seen in patients with chronic fatigue syndrome and may help to explain the symptom complex.

ELECTROAUTONOMOGRAPHY: A DIAGNOSTIC TOOL FOR CFS - E. LERNER

Research Autonomography, Russian Academy of Science, Moscow and CLB Electronics, The Netherlands

Electroautonomography (EAG) is proposed as a method to diagnose CFS and other disorders of the autonomous nervous system (ANS). The essence of the EAG is the recording of the skin potentials on both hands and feet, the graphs are then analysed and interpreted. An electroautonomograph has been developed by the author and is now patented for all countries in the world. The device has been tested at several universities in The Netherlands with positive results.

An EAG reveals the state of the ANS

1.Normotonia : characterized by a curve with spontaneous potentials of 1 to 2 mV at 2 to 16 waves per minute. External stimuli (light, sound) evoke a mono- or biphasic skin potential of 1 to 5 mV.

2.Sympatheticotonia : a curve without spontaneous potentials. Stimuli evoke monophasic potentials of 0.5 to 1 mV.

3.Parasympatheticotonia : a curve with high potentials, 2 to 6 mV and higher and with a frequency of 2 to 16 cycli per minute. Stimuli evoke a potential of 4 to 10 mV, mono- or polyphasic.

Ten CFS patients have been studied recently with an electroautonomograph. The results show significant irregularities of the ANS of CFS patients compared to healthy individuals, illustrating that CFS is a disorder of the autonomous nervous system. Eight of the patients have parasympathicotonia with high spontaneous potentials (4 to 10 mV). There are non-symmetrical curves (at the left/right of the extremes), much higher potentials on the feet than on the hands, non-adequate big and irregular potentials after giving a stimulus.

Two patients have sympatheticotonia with no spontaneous potentials shown in the graphs.

PYRIDOSTIGMINE-INDUCED GROWTH HORMONE RESPONSES - EVIDENCE FOR CHOLINERGIC SUPERSENSITIVITY IN CFS - 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 Barthoioinew's Hospital, United Kingdom

OBJECTIVES : Acetylcholine (ACH) supersensitivity is associated with depression. This study is undertaken to assess the ACH function in patients with chronic fatigue syndrome.

METHODS : sixteen healthy subjects (8 males and 8 females) and twelve patients (six male and six females) with CFS were tested. Subjects presented at 9.00 am following an overnight fast. Pyridostigmine 120 mg orally was administered at 0 min. Blood samples were taken at 0, +60, +120, +180, and +240 min for measurement of growth hormone. Delta growth hormone (DGH difference : between baseline values and the maximum increase postpyridostigmine administration) measures were used to compare the responses. Student's t test was used where appropriate. Results were expressed as mean # SEM.

RESULTS : all subjects responded to pyridostigmine with an increase in plasma growth hormone. A mean DGH in CFS of 17.07 pm 2.57 mU/l was significantly elevated compared to a mean DGH of 6.84 # 1.26 mU/l in healthy controls (P = 0.0024).

CONCLUSION : this study also demonstrated acetylcholine receptor supersensitivity in patients with CFS as reported previously in depressives.

BACLOFEN-INDUCED GROWTH HORMONE RELEASE - DOES THE GABA PLAY ANY ROLE IN THE PATHOPHYSIOLOGY OF CHRONIC FATIGUE SYNDROME ? - 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 the involvement of the GABAergic system in depression. In the present study the sensitivity of GABA-B receptors was assessed via the growth hormone response to baclofen to find out the role, if any, of GABAergic mechanisms in the pathophysiology of CFS.

METHODS : twelve healthy controls (mean age 35 years) and 12 patients (mean age 39 years) who met CDC criteria for CFS were recruited in this study. All gave their informed consent to participate in the study. The experiment was performed in the morning after an overnight fast. Serial blood samples were taken for growth hormone estimation at 0, +30, +60, +90, +120 and +180 min after the administration of baciofen (20 mg orally). Change in growth hormone (DGH) was measured by subtracting the baseline GH level from the peak value after baclofen administration.

RESULTS : the overall GH levels rose after bac]ofen administration. The response was not different significantly in patients with chronic fatigue syndrome (mean DGH = 12.6 mU/I) from controls (mean DGH = 10.8 mull), P = 0.580.

CONCLUSION: no difference was found between healthy subjects and CFS patients with regard to the GH response to acute administration of baclofen suggesting GABAergic mechanisms are not involved in the pathophysiology of CFS.

ARE HEALTH CARE PROFESSIONALS MORE PRONE TO CFIDS ? - M.M. SHANNON

Representing : Medical Professionals with CFIDS, Cardiff, USA

Anecdotal evidence suggests that the preponderance of those affected by CFIDS and related immune disorders are health care professionals. Clearly, considerably more epidemiological evidence is required if we are to understand the incidence and prevalence of this emerging entity in the population. Is it largely a "White woman's disease", or does it affect, but remain largely undetected, among other racial and ethnic groups ? Which men are affected and why ? Is it more common among medical workers (nurses, respiratory therapists, Md.'s, lab techs) than other professions ? Is it because the medical profession consists mostly of women who are on the front line with greater exposure to environmental toxins, viruses, bacterias, or microplasma, combinations, or other factors ?

Emerging evidence indicates that CFIDS may trigger a variety of autoimmune diseases - diseases which tend to be more prevalent among women than men. Thus, steroidal sex hormones are likely to play an important and integral role in the development of CFIDS and other immune disorders. What is clear is that epidemiological data are required to guide hypothesis generation and hypothesis testing. In an area of shrinking research resources, we must know where to focus research action.

Evidence gathered to date has already shown us that early detection and intervention can mitigate the course of the disease, e.g., the earlier the intervention, the more complete and rapid the recovery (if there is to be any recovery). Yet we need a clearer and more comprehensive understanding of the genesis and course of CFIDS and related disorders if we are to avert it entirely, or to intervene at the earliest stages when recovery is more easily achieved. Furthermore, data gathered from CFIDS investigations will undoubtedly lead to discoveries in related diseases and disorders.

FURTHER EVIDENCE FOR BIOCHEMICAL DEFECTS IN THE 2-5A SYNTHETASE/RNASE L AND PKR PATHWAYS IN CHRONIC FATIGUE SYNDROME -- R.J. SUHADOLNIK, D.L. PETERSON, K. O'BRIEN, C.V.T. HERST, W. PFLEIDERER, R. CHARUBALA, N.L. REICHENBACH, N. KON, M.E. ADELSON

Temple University School of Medicine, Philadelphia, Pennsylvania, USA; Sierra Internal Medicine, Incline Village, Nevada, USA

The objective of the studies described is to continue the characterization of immunological and biochemical abnormalities in the 2', 5'-oligoadenylate [2-5A] synthetase/RNase L and p68 kinase [PKR] antiviral pathways in chronic fatigue syndrome [CFS].

Previous studies from this laboratory have demonstrated pronounced dysregulation in several key components of these antiviral and antiproliferative pathways [Suhadoinik et a]., Clin. Infectious Dis. 18: S96-104 (1994); In Vivo 8: 599-604 (1994)]. Statistically significant differences in biologically active 2-5A, RNase L activity and PKR expression have been observed in extracts of peripheral blood mononuclear cells from individuals who meet the CDC criteria for CFS compared to healthy controls. Studies have been conducted with (i) polyclonal and monoclonal antibodies to 2-5A synthetase, the 80 kDa RNase L and PKR and (ii) azido ATP and 2-5A photoaffinity probes.

These studies provide further evidence for a dysregulated immune state in CFS. Such dysregulation in the 2-5A synthetase/RNase L and PKR pathways is consistent with a role for virus infection in the pathogenesis of these chronic fatigue syndrome patients.

ABNORMALITY OF ADRENAL FUNCTION IN THE PATIENTS WITH CFS: THE DECLINE OF 17-KETOSTEROID SULFATE (17-KS-S) - K. YAMAGUTI (1), H. KURATSUNE (1), T. MACHII (1), S. KODATE (2), T. KITANI

1 Hematol & Oncol.,Osako University MedicaI Schoo, Osaka, Japan
2 Sumitomo Metal Blosdence, Kanagawa, Japan

The etiology of CFS has not yet been clarified though many investigators have made efforts to resolve this problem using a number of approaches. In 1991, Demitrack et al. reported that patients with CFS might have impaired activation of the hypothalamic-pituitary-adrenal axis. During psychological stress, it is also well known that serum cortisol concentration and urinary 17-hydroxycorticosteroid (17-OHCS) excretion increases, while urinary 17-ketosteroid sulfate (17-KS-S) excretion decreases.

To investigate the endocrine relationship between psychological and physical stress, and CFS, we compared the values of urinary 17-OHCS (mg/g creatinine) and 17-KS-S (mg/g creatinine) excretion while sleeping at night in 49 patients with CFS (26 # 3.6 years old) and in 35 normal age matched controls (27 # 3.9 years old).

We found that the level of 17-KS-S was significantly lower in CFS patients than the normal controls (1.54 # 1.04 in CFS vs 3.01 # 1.04 in control, p < 0.001), while the level of 17-OHCS was around the same as the controls (4.31 # 1.26 in CFS vs 4.22 # 0.77 in controls). To clarify the abnormality of 17-KS-S in the patients with CFS, we measured the serum level of ACTH, cortisol, 17-OH pregnenolone, dehydroepiandrosteron (DHEA), DHEA-suifate (DHEA-S) and androstenedione in 14 patients with CFS after overnight fasting. The level of ACTH, cortisol, 17-OH pregnenolone, dehydroepiandrosteron (DHEA), DHEA- sulfate (DHEA-S) and androstenedione in 14 patients with CFS after overnight fasting. The level of ACTH, cortisol, 17-OH pregnenolone and androstenedione in most patients with CFS was within the range of mean # 2SD of normal controls, while the level of DHEA decreased in some patients and the level of DHEA-S decreased in most patients with CFS.

These results suggest that the decline of urinary 17-KS-S excretion while sleeping at night in the patients with CFS was mainly due to the decline of serum DHEA-S. These abnormalities found in CFS are quite different from those found in patients with mental and physical diseases reported previously.

 Session IX CFS : Treatment

A REVIEW OF THE USE OF ANTIVIRAL AND IMMUNOMODULATING DRUGS IN THE TREATMENT OF CHRONIC FATIGUE SYNDROME - K. DE MEIRLEIR

Dept. Human Physiology, HILOK,, Ville Universiteit Brussel, Brussels, Belgium

As some evidence exists that a range of viruses can induce a chronic fatigue syndrome antiviral drugs have been used in the post to treat this disorder. Proven changes in the immune function, often with upregulation of this system have prompted scientists to use immunomodulators in the treatment of CFS.

In this review we will give an overview of controlled and uncontrolled trials with various drugs. Studies with Acyclovir, Amantadine, Kutapressin and Isoprinosine have yielded negative or inconclusive results. A look at the different studies in which immunogiobulines were given as a treatment for CFS show either a favorable or no effect. Uncontrolled trials with Transfer Factor and Lentinan need to be repeated in a double blind cross over placebo design.

Other treatments as beta-carotene, high dose Vitamin B12 and DHEA are reported to be effective treatments from clinical practice but lack vigourous scientific testing. A randomised placebo controlled study with EFA supplementation as active treatment which showed excellent results needs repetition, preferably in a multicenter large study.

Finally, the 3 studies performed with Ampligen R, a drug with antiviral and immunomodulating properties are discussed. In all three some patients are responders, others non responders, but at this moment it is unclear why this occurs. Further analysis of the data in this study may contribute to shed light on the pathogenesis of CFS.

A NEW MODEL FOR HANDLING CFS-PATIENTS AT AN OUT PATIENT DEPARTMENT OF INFECTIOUS DISEASES IN SWEDEN - R. ENGQVIST, C. HEDENSTEDT, B. EVENGARD, G. LINDH, L. LINDQVIST, R. OLIN ME Clinic, Department of Infectious Diseases, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden

OBJECTIVES : to increase the quality in taking care of patients with suspect chronic fatigue syndrome (CFS/ME) at a policlinic of an infectious disease clinic at a university hospital in Stockholm, Sweden.

BACKGROUND : an increasing number of patients, attending the clinic for infectious diseases, fulfilled the criteria for CFS/ME. The knowledge of this illness was, at that time, comparatively little in Sweden. Patients were too often dissastisfied giving rise to a nomadic behaviour in the health system. They felt that almost no one really believed in them.

METHODS : we started up a special outward unit, so called "the ME-unit", in September 1993, and created a special rehabilitationprogram for this group of patients. The "program" consists of 3 parts, all in fixed small groups.

1. ME-school : the patients get lectures in different touching subjects of the ME-syndrome and the problems that are its consequence. 2. Hydrotherapy - movement training of low intensity and relaxation at the end in heated water. 3. Relaxation training - basic relaxation in order to help the patients to be able to train at home.

RESULTS : almost all patients and their relatives thought, that they had a better life quality in spite of the illness, after they had attended our unit and participated in the program. We have learned a lot from the patients and have started new studies on the ME-syndrome often in international collaboration.

ACYLCARNITINE METABOLISM IN MAMMALIAN - H. KURATSUNEI.(1,3), K. YAMAGUTI (1), Y. WATANABE (2,3), M. TAKAHASHI(4), I. NAKAMOTO (1), T. MACHII (1), G.B. JACOBSON (3,5), H. ONOE (2,3), K. MATSUMURA (2.3), S. VALIND (3,5), B. LANGSTROW. (3,5), T. KITANI (1)

1 Hematol. and Oncol., Osaka University Medical School
2 Dept. of Neuroscience, Osaka Bloscience Inst.
3 Subfemtomole Biorecognition Project, Res. Develop. Co. of Japan
4 Asahl Chem. Industry Co., LTD, Res. & Develop Dept., Japan
5 Uppsala University PET Centre, Uppsala, Sweden

Acylcarnitine (ACR) has been reported to have several important pharmacological properties, including effects on the survival of adult rat sensory neurons, effects on rat brain energy and phospholipid metabolism, improvement of performance in spatial learning tasks in aged rats, prevention of age-dependent structural alterations in rat peripheral nerves and inhibitory effects on apoptosis. Recently, we found serum ACR deficiency without free carnitine (FCR) abnormality in patients with chronic fatigue syndrome (CFS). However, it is not known how and where most of this serum ACR is metabolized in the body.

In this study, carnitine metabolism during starvation and soon after refeeding was studied by measurement of FCR, ACR and total carnitine (TCR) concentrations in serum, skeletal muscle, heart, liver and brain in mice. Starvation caused marked increases in the concentration of serum ACR, and of acid-soluble ACR and TCR in the liver, and the increase of serum ACR disappeared quickly after refeeding with a concomitant marked increase in level of acid-soluble TCR in the liver. By use of positron emission tomography, a marked increase in [2-11C]-acetyl-L-carnitine uptake in the liver was observed after administration of glucose accompanying the decrease of serum ACR in rhesus monkey. These findings suggest that the mammalian liver can synthesize and release large amounts of ACR at times of danger in energy metabolism, and immediately salvage and conserve the unused ACR when the state of energy metabolism is improved by taking meals.

Our current studies suggest that the actual uptake of acetyl carnitine in the brain is higher than considered previously. Judging from these findings, serum endogenous ACR might have a significant role in the mammalian, and serum ACR deficiency in CFS might be related with its pathogenesis.

TRIAL OF A SELECTIVE ACETYL CHOLINESTERASE INHIBITOR, 6 ALANTHAMINE HYDROBROMIDE, IN THE TREATMENT OF CHRONIC FATIGUE SYNDROME - E. SNORRASON (1), A. GEIRSSON (1), K. STAFANSSON (2)

1 Dept. of Psychiatry and Internal Medicine, University Hospital, landsspitalinn, Reykjavik, Iceland
2 Divison of Neuropathology, Dept. of Neurology, Boston Beth Israel Hospital, Harvard Medical School, Boston, USA

The purpose of the study was to search for means of diminishing the plight of patients with chronic fatigue syndrome (CFS) and to test the hypothesis that a cholinergic defect is central to the pathogenesis of CFS. Forty-nine patients who fulfilled consensus criteria for CFS were treated the acetylcholinesterase inhibitor, galanthamine hydrobromide.

Thirty nine patients finished the study according to the protocol with 43 % reporting 50 % improvement, in fatigue, myaigia and sleep and 70 % reporting 30 % improvement whereas patients in the placebo group reported only 10 % improvement in the same parameters of CFS. The improvement of patients on galanthamine was in most cases gradual and only reached significance for the group after four to eight weeks. The improvement was stable and no patients who reported over 50 % improvement on galanthamine relapsed to a pretrial level of any symptom. One of the most surprising effects was the dramatic improvement of sleep disturbances that occurred in most patients on this medication : more than 60 % of patients that finished the study reported over 70 % improvement in sleep deficit. If this is indeed true it would be the first demonstration of a drug that can be used to correct a sleep disturbance that also influences a specific stage in normal sleep.

The most common adverse effect of galanthamine, as given in this study was mainly nausea that was dose dependent and reversible. Galanthamine hydrobromide is relatively safe and appears to be an effective medication against many symptoms of CFS. But the positive results of this study have to be interpreted cautiously because of methodological limitations of this trial. First this study was originally organized as a double blind, placebo controlled trial but was changed to an optional crossover after two weeks of treatment. Also the adverse effects of the active drug in 30 % of patients would compromise the double blind.

With these limitations in mind it is all the same tempting to conclude that this study lends an indirect support to our hypothesis that a cholinergic deficit may play a role in the pathogenesis of the syndrome.

AN OVERVIEW OF CLINICAL EXPERIENCE IN THE U.S.A. WITH AMPLIGEN (*) (POLY:POLY C12U) IN THE TREATMENT OF CHRONIC FATIGUE SYNDROME (CFS) - D.R. STRAYER, W.A. CARTER

Medical College of Pennsylvania, Hahnemann University and hemispherx Blopharma, Philadelphia, USA

Double-stranded RNAs are bifunctional molecules with both antiviral and immunomodulatory activities. A specifically configured RNA drug, poly (I): poly (C12U), has been generally well tolerated clinically, thus permitting its chronic administration. Poly (l):poly (C12U) was initially tested in an open-label study of 15 subjects meeting the CDC case definition for CFS (J CFS. 1, 35, 1995). Significant improvement in performance during exercise treadmill testing was seen during 24 weeks of treatment and subjects showed a reduction in,HHV-6 reactivation and a trend for improved cognition. Based on these results, a randomized, placebo-controlled, double-blind, multicenter study was performed (Clin Infect Dis. 18, S88, 1994). The primary clinical endpoint was physical performance as determined by Karnofsky Performance Score and secondary endpoints included perceived cognitive performance using the cognitive deficit subscale of the SCL90-R test, levels of activities of daily living (ADL), and exercise treadmill performance.

Ninety-two subjects meeting the CDC case definition of CFS were randomized to receive either poly (l):poly (C12U) or placebo. Following 24 weeks of treatment, subjects receiving poly (l):poly (C12U) showed both global performance and cognitive improvement as compared to placebo. In particular, the poly (l):poly (C12U) subjects showed increased Karnofsky performance scores (p < 0.03), greater ability to do work during exercise treadmill testing (p = 0.01), enhanced performance of activities of daily living (p < 0.04), reduced cognitive deficit (p = 0.05), and required less use of other medications (p < 0.05).

In conclusion, poly (1):poly (C12U) has been generally well tolerated and has shown clinical activity with increases in performance and cognition in two separate clinical trials conducted in the United States.

FLUOXETINE IN CHRONIC FATIGUE SYNDROME: A RANDOMIZED, DOUBLE-BLIND PLACEBO-CONTROLLED STUDY -  J.H.M.M. VERCOULEN (1), C.M.A. SWANINK (2,3) , F.G. ZITMAN, S.G.S. VREDEN (2), M.P.E. HOOFS (1), J.F.M. FENNIS (2), J.M.D. GALAMA (3), J.W.M. VAN DER MEER (2). G. BLEIJENBERG (1)

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
4 Dept. of Medical Psychiatry, University Hospital Nijmegen, The Netherlands

Antidepressant therapy is frequently applied in patients with CFS. Fluoxetine is recommended in preference to tricyclic agents because of fewer side-effects. However, there are no randomized, placebo-controlled, double-blind studies demonstrating the effectiveness of antidepressant therapy in chronic fatigue syndrome.

In the present study, two groups of patients were included : a depressed CFS-group (N = 44) and a nondepressed CFS-group (N = 52). In each group participants were assigned in a randomised, double-blinded manner to receive either fiuoxetine (20 mg once a day) or placebo. The effect of fluoxetine was evaluated by a multi-dimensional assessment method, including questionnaires, self-observation lists, standardized neuropsychological tests and a motion-sensing device (Actometer).

When compared to the placebo group, at posttreatment, patients treated with fluoxetine did not improve in fatigue severity, depression severity, functional impairment, sleep disturbances, neuropsychological functioning, and cognitions, or showed an increase in physical activity. At posttreatment, fluoxetine was never superior to placebo. The lack of effect on depressive symptoms suggests that processes underlying the presentation of depressive symptoms in CFS may be different from underlying processes in patients with major depressive disorder.

Fluoxetine in a 20 mg dose daily does not have a beneficial effect on any dimension of CFS.
 
 

NATURAL COURSE OF CFS AND ITS PREDICTORS - G. BLEIJENBERG (1), J.H.H.M. VERCOULEN (1), E. BAZELMANS (1), C.M.A. SWANINK (3), J.F.M. FENNIS (2), J.M.D. GALAMA (3), J.W.M. VAN DER MEER (2)

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

Little is known about the natural history of Chronic Fatigue Syndrome. Older studies do not concern CFS patients, but only patients with fatigue, with different criteria. The setting where the patients were seen was primary care or specialists unit. Actually, studies in which only natural course - that is course without any intervention. - has been investigated are not present.

In all studies on natural history patients received some form of treatment, varying from optimistic reassurance, clinic visits, immunologic therapy to cognitive behaviour therapy. Improvement rates differ from 13 % to 57 %; recovery rates from 3 % to 42 %. In the different studies different predictors were found. Psychological factors as the presence of an emotional disorder, physical attributions, lower level of activity and negative self-efficacy has been mentioned as predictors of the course besides a long duration of complaints, a higher age and member of a patient organization. No somatic predictors were found.

There is a great need to develop risk profiles to identify in an early stage those patients with a chance of maintaining chronic fatigue.

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 a].). 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 %.
 
 

"GULF WAR SYNDROME": AN OVERVIEW - P.H. LEVINE 6130 Executive Blvd. EPN/434, Rockville, USA

In 1990/1991, an approximately 697,000 U.S. service members joined forces from a number of other countries in a joint m ' ilitary operation in the Persian Gulf. Designated Operations Desert Shield/Desert Storm (ODS/S), this action involved exposures to a number of diverse environmental agents, such as oil, fire smoke, diesel and tent/heater fumes, and leishmaniasis, as well as to several preventive vaccines and medications.

Subsequent to ODS/S, a number of veterans complained of a variety of symptoms, primarily fatigue, joint pain, headache, sleep disturbance, difficulty concentrating, muscle pain and depression, all being important features of chronic fatigue syndrome (CFS). While early discussions emphasised the similarity of a postulated Gulf War Syndrome (GWS) and CFS, subsequent reports have failed to define consistent findings and criteria and the existence of a specific syndrome has been questioned.

In this report the information available from a series of studies will be reviewed with particular attention to the groups affected (U.S. and U.K. participants rather than other troops, U.S. reservists rather than active duty soldiers, etc.).

A CDC INVESTIGATION OF ILL PENNSYLVANIA PERSIAN GULF WAR VETERANS -K. FUKUDA

Mall Stop A15, Atlanta, USA

Since the return of approximately 700,000 U.S. service personnel from the Persian Gulf War (PGW), anecdotal reports have circulated widely about "unexplained" health problems among them and their families. In December 1994, the Centers for Disease Control and Prevention began a three stage investigation of a reported "mystery' illness in a group of PGW veterans. Two physicians reported thatat least60 PGWveterans, all from a single Pennsylvania Air National Guard unit, had developed an illness characterized by irritable bowel syndrome, dermatitis, arthraigia, and 17 other signs and symptoms.

In stage 1, we evaluated a sample of 59 ill Pennsylvania PGW veterans, including those from the index unit and others from the local area, by interview, questionnaire, examination, and medical record review. We documented several chronic symptoms and isolated disorders among them, including one case each of vescerotropic leishmaniasis and Addison's Disease, but found no objective abnormalities on a consistent basis.

In stage 2, we surveyed approximately 4000 persons in the index ANG unit, and three other comparison units. Preliminary. findings showed the prevalence of several chronic symptoms to be substantially higher in those who were deployed than those who were not. Current analysis of symptoms is directed at devising a case definition of illness for use in subsequent studies.

In stage 3, we have collected extensive epidemiologic and clinical data, including specimens (urine, stool, and blood), from 170 ill and well PGW veterans in the index unit. Testing of specimens and analysis to identify risk factors is underway.

PRELIMINARY PREVALENCE DATA ON CHRONIC FATIGUE SYNDROME (CFS) AND MULTIPLE CHEMICAL SENSITIVITY (MCS) IN PERSIAN GULF VETERANS - B. NATELSON. N. FIEDLER, T. POLICASTRO, H. KIPEN

VA Medical Center and University of Medicine and Dentistry, NJ, USA

Because 4,of the 5 most frequently reported complaints of Persian Gulf veterans constitute part of the case definition of CFS, we hypothesized an increased rate of CFS in this group. Bates et al. have reported a prevalence of CFS in 1000 consecutive general medical clinic visitors of # 1 %. Also, various anecdotal reports have suggested a substantial presence of chemical sensitivity symptoms leading us to further hypothesize an increased rate of MCS in this group.

To evaluate these possibilities, we sent questionnaires to 229 andomiy selected veterans on the VNs Persian Gulf Registry. The Registry is comprised of both symptomatic and asymptomatic Gulf veterans (83 % and 17 % respectively). 52 % of veterans responded, 16 of the responses were ineligible because of medical illnesses which could produce fatigue. Of the 104 replies available for analysis, 1 0 % fulfilled the decreased activity and symptom criteria of the 1988 case definition of CFS. In addition, 26 % of the group noted they were especially sensitive to certain chemicals, and 4 % reported that this sensitivity had produced at least 3 of 4 lifestyle changes; these complaints indicate the presence of MCS, a symptom complex reported predominantly in women.

Although our data are only based on self report, the prevalence we have found for CFS and MCS appear high in this predominantly male sample of veterans; this suggests that something about serving in the Gulf substantially increased the risk for developing CFS and MCS.

Supported by VA funds establishing a Gulf War Research Center

SKELETAL MUSCLE IN PERSIAN GULF VETERANS - K. VANDENBORNE, G. WALTER, D. LENROW, J.S. LEIGH, A. FISHMAN

Dept. of Rehabilitation Medicine, University of Pennsylvania, USA

Since their return from the Persian Gulf War a large number of veterans have reported symptoms consistent with Chronic Fatigue Syndrome (CFS). Among the most common symptoms are fatigue (23.3 %), skin rash (21.2 %) and muscle and joint pain (1 8.0 %) Because of the high incidence of muscular complaints we are currently studying muscle function in Persian Gulf veterans with severe CFS.

Muscle function is evaluated using a variety of measurements including Magnetic Resonance Spectroscopy, Magnetic Resonance lmaging, muscle biopsies, electrodiagnostic testing and isometric and isokinetic functional tests. Sophisticated 31P-Magnetic Resonance Spectroscopy techniq ues are implemented in order to identify possible defects in the muscie's in vivo ability to supply energy.via aerobic and anaerobic means, as well as its ability to manage energy during contraction.

In contrast, Magnetic Resonance Imaging techniques are used to evaluate the morphological properties of skeletal muscle in Persian Gulf veterans with severe CFS. In particular, we look for indications of muscle fibrosislmuscle damage, abnormal amounts of fat infiltration and other soft tissue lesions. In addition, 3D-Magnetic Resonance lmaging procedures are being used to determine the contribution of simple muscular atrophy to the decreased muscle function.

Finally, in order to quantitatively assess the degree of muscle weakness and fatiguability in the Persian Gulf veterans, strength and endurance measurements are being performed. Both measurements are performed using standard isokinetic and isometric measures as well as electrical stimulation.
 
 

EVALUATION OF A PROGRAMME FOR PATIENTS WITH CFS - A PILOT STUDY - P. ASBRING

Unit of Health Services Research and Development, Novum, Sweden

BACKGROUND : at the ME-clinic, Department of Infectious Diseases, Huddinge University Hospital, Sweden, there is a rehabilitation programme for patients with CFS/ME. The Unit of Health Services Research and Development, Huddinge, has participated in the evaluation of their programme that consists of 8 educational group sessions, relaxation techniques and gymnastics in warm swimmingpool under guidance of a physiotherapist. It also implies a close contact with the ME-team, especially a nurse and the doctors, during 6 months.

OBJECTIVES : the main objectives of the study were to describe the effects of the ME-programme on the participating patients, estimate their health care consumption, employment rate, sick leave and quality of life before and after. Another objective was to describe the effects on the patient's own sacrifies.

METHOD : the study is based on a questionnaire which cover the patients perceptions of the programme, a comparison of the objectives studied before and after the intervention and also includes open ended questions that covers some general topics. This questionnaire was sent out in April 1994 to 20 patients with a clear diagnosis of CFS, that participated in the programme during the spring of 1993. The patients were followed retrospectively two years back in time from the first visit at the ME-clinic and one year after the rehabilitation programme.

RESULTS : response rate was 90 % (18 patients). 12 were women and 6 men. Mean age of the respondents were 38 years. The patients had an episode of illness, until April 1994, on an average of 38 months. 17 months had passed, in average, between the first contact with the health care system and the first contact with the ME-clinic. All patients, except one, experienced increased knowledge about the disease during the programme and all were satisfied in general and thought that their participation had affected the course of event of their disease in a positive direction. The patients had fewer visits to physicians after helshe had come in contact with the ME-clinic. Visits to alternative practitioners were also reduced. The sick-leave (days) were slightly increased duringlafter the programme. Direct costs for health care consumption, due to the disease, decreased for most patients, but their private economy in total became worsened during this period. The overall quality of life improved after participation in the programme. Many patients have also experienced increased self-knowledge, humbleness and noticed that their own capacities, like optimism, have had positive effects in their healing process.

IQ ABNORMALITIES ASSOCIATED WITH CHRONIC FATIGUE SYNDROME IN REPEATED WAIS-R TESTING - S. BASTIEN. D.G. WATSON, D. PETERSON

Clinical Psychology, California, USA

OBJECTIVE: to evaluate IQ changes in clinically defined patients with CFS.

METHODS : forty patients meeting the CDC criteria for chronic fatigue syndrome (CFS) had IQ testing at least twice during the course of their illness. Other diseases were ruled out with extensive medical testing and evaluation. The repeated IQ tests were done for several reasons : clinical questions or concerns over intellectual deterioration; issues of disability or Workers' Compensation; or evaluation for possible treatment modalities. The Wechsier Adult Intelligence Scale, Revised (WAIS-R) was administered. Norms were used from Robert Heaton, Ph.D. et al.* These new norms adjust for age, sex, and education, yielding T-scores with impairment levels, comparing parameters to normal populations.

RESULTS : at the lowest point, Performance IQ's (PIQ) were impaired (adjusting for age, sex and education), indicating a greater loss in non-verbal abilities. Verbal IQ (VIQ) was far less impaired. VIQ/PIQ differences were significant. An attention-concentration factor is found to be most impaired. Another factor related to visual perception and visual-motor speed is impaired but to a lesser extent.

SUMMARY : the results of this study suggest associated 10 loss in CFS. Repeated IQ measures over time indicate definite shifts in intellectual functioning during the course of the illness.

* R. Heaton, I. Grant, C. Matthews, Comprehensive norms for an expanded Halstead-Reitan battery: demographic correcuons, research findings and clinical applications. Psychological Assessment Resources, Inc., Odessa, Fiodda, 1991, and R. Heaton, I. Grant, C. Matthews, Comprehensive norms for an expanded Halstead-Reitan battery: a supplement for the Wechsler Adult Intelligence Scale - Revised. Psychological Assessment Resources, Inc.,Odessa, Flodda, 1992

THE PREVALENCE OF CFS IN THE NETHERLANDS - E. BAZELMANS (1), J.H.H.M. VERCOULEN (1), C.M.A. SWANINK (3), J.F.M. FENNIS (2), J.M.D. GALAMA (3), J.W.M. VAN DER MEER (2), G. BLEIJENBERG (1)

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

We studied the prevalence of the chronic fatigue syndrome (CFS) as well as the primary fibromyaigy syndrome (PFS) by sending a postal questionnaire to all the 6657 general practitioners in the Netherlands. Our purpose was not only to get an indication of the prevalence of CFS and PFS, but also to inform all general practitioners about this syndrome. Sixty percent (4027) of the general practitioners returned the questionnaire. Of all the general practitioners, 27 % said not to have any CFS patient, 23 % said to have 1 CFS patient, 21 % to have 2 CFS patients, and 30 % said to have 3 or more CFS patients in their practice.

Concerning PFS patients 17 % of the general practitioners has none PFS patient, 18 % 1 PFS patient, 18 % 2 and 47 % more than 3 PFS patients. With a mean practice of 2486 patients, we come at a prevalence of 112 CFS patients and 157 PFS patients per 100.000 persons. Of the CFS patients 81 % is women and 55 % of these CFS patients are between 24-44 years old. Of the PFS, patients 87 % is women and 48 % of the PFS patients are between 24-44 years old. We do have reasons to believe that the prevalence of 127 CFS patients per 100.000 persons in the Netherlands is an underestimation..

ATTENUATED DHEA RESPONSE TO I.V. ACTH INJECTION IN PATIENTS WITH CHRONIC FATIGUE SYNDROME - P.DE BECKER (1), K. DE MEIRLEIR (1), E. JOOS (1), J. SMITZ (2), B. VELKENIERS (3), L. DE HAUWERE (1), L. WETS (1)
1 Human Physiology, HILOK, Vrije Unlversiteit Brussel, Brussels, Belgium
2 RIA Laboratory, A.Z. V.U.B., Brussels, Belgium
3 Department of Endocrinology, A,Z. V.U.B., Brussels, Belgium

OBJECTIVE : Demitrack et al. (1991) reported an altered activity of the hypothalamic-pituitary-adrenal (HPA) axis in CFS patients, more specifically a mild giucocorticoid deficiency. Dehydroepiandrosterone (DHEA) is a major adrenal adrenogenic secretory product. Some have reported lower basal serum DHEA levels in CFS. As DHEA may have an important regulatory function in cell-mediated immune response, it seemed important to obtain information on the responsiveness of this hormone to erogenous ACTH.

METHODS : from the outpatient clinic of the Academic Hospital in Brussels we recruited 11 patients (age range, 18-45 years; mean pm SD, 33.54 pm 9.19) who met the CDC criteria for CFS. All patients had been investigated before entering the trials to exclude alternative medical diagnosis and had cell mediated immune function measured by T lymphocyte subset analysis. Patients with doubt of primary psychiatric disorders were excluded. Controls were 11 age- and sex-matched healthy individuals (age range, 23-45 years; mean # SD, 32.81 # 7.91). All were free of major medical or psychiatric conditions. All the tests were performed between 9h30 and 10h30 a.m. After injecting of 1 ml/0.25 mg Tetracosactide (SynacthenR) I.V., blood samples for measurement of DHEA were taken at 0, 15, 30, 45 and 60 minutes. Statistical evaluation of DHEA levels was performed by,analysis of variance (ANOVA) with repeated measurements and Student's t test. A p value < 0.05 was considered statistically significant.

RESULTS : compared to controls (A), CFS patients (B) do not show a difference in basal serum DHEA levels, A: (7.64 UG/L # 4.48 UGIL) versus B: (6.16 UG/L # 3.08 UG/L); p = 0.32. Percent increase in DHEA compared to baseline was lowerin CFS patients (mean # SD, 181.95 % # 48.54) compared to controls (mean # SD, 258.40 % # 55.7); p = 0.01.

CONCLUSION : in contrast to the findings for basal cortisol levels in blood, CFS patients do not have lower basal DHEA levels compared to normal controls. However CFS patients show a blunted DHEA response to a standard dose of exogenuous ACTH. As other observations suggest a protective role for DHEA in viral infection, this finding may have clinical importance.

EVIDENCE FOR IMMUNE ACTIVATION IN A SUBSET OF CHRONIC FATIGUE SYNDROME PATIENTS - C. DEMANET (1), E. J00S (2), P. DE BECKER (2), B. FISCHIER (3), K. DE MEIRLEIR (2)

1 Dept. of Hematology, Academic Hospital of the Free University of Brussels, Brussels, Belgium
2 Dept. of Human Physiology, Academic Hospital of the Free University of Brussels, Brussels, Belgium
3 Dept. of Psychology, Academic Hospital of the Free University of Brussels, Brussels, Belgium

We analysed the cellular immune status of 149 patients with the chronic fatigue syndrome (CDC criteria).

Disease controls consisted of patients with psychiatric disorders (n = 26), fibromyaigia (n = 17), combined fibromyaigia and CFS (n = 11), a CFS-like group (n = 17) and normal healthy controls (n = 40). The cellular immune status was evaluated using an extensive panel of monoclonal antibodies on flow cytometry with dual immunofluorescence.

Only minor immune abnormalities were detected : increase of CD2+CD25 cells, imbalance of virgin/memory CD4 T cells, decrease of the CD8+CD11b+ subset and natural killer cells. The B cell compartment was not involved in this disease. Further analysis revealed that the increase of the CD4+CD45RO+ memory T cell subset in CFS patients could not be attributed to the patient population as a whole but rather to a subset of CFS patients. Indeed, 25 % of the patients exhibited high numbers of memory T-cells. These cells require less stringent requirements for maximal proliferation and cytokine secretion than naive T cells. Low levels of antigen are enough to trigger there lease of cytokines in this cell population. This could explain the symptomatology in a subgroup of CFS patients based on clinical effects of interferons and interieukin-2.

Whether the high level of these memory T cells in a subset of CFS patients is a characteristic marker of recent disease exacerbation, and not of the chronic state, will only be clarified in longitudinal studies. Of all the disease controls, these high levels memory T cells were only detected in fibromyaigia patients.

BORNA DISEASE VIRUS AND CHRONIC FATIGUE SYNDROME -- J.W. GOW, W.M.H. BEHAN, J.C. DE LA TORRE, K. SIMPSON, D. KAY, M.M. McGILL, P.O. BEHAN

Department of Pathology & Neurology, University of Glasgow, Southern General Hospital, United kingdom,
The Scripps Institute, La Joila, California, USA

OBJECTIVES : Borna disease virus (BDV) can cause acute, subacute or chronic infections, producing disturbances in behaviour and cognitive functions in various animal species. Peripheral blood leukocytes from patients with acute and chronic depression have recently been shown to contain BDV nucleic acid. This study was undertaken to determine whether tissues samples from patients with chronic fatigue syndrome (CFS) contained BDV nucleic acid.

METHODS : the following samples from patients with CFS were examined for BDV nucleic acid: tissue from the brainstem and hypothalamus of one case, 10 cerebrospinal fluids, 25 peripheral blood leukocyte preparations (including 8 from agricultural workers) and 21 sera. The control material was central nervous system tissue from three patients with depression, 10 cerebrospinal fluids from patients with lumbar disc problems and peripheral blood leukocytes and sera from 8 patients with depression and 10 normal healthy controls. Nested reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out on RNA isolated from the samples, followed by southern blot analysis of the PCR products and hybridisation with an end-labelled oligonucleotide probe. Three serum samples from patients with CFS were also tested for the presence of BDV antibodies by immunofiuorescence (IF).

RESULTS : one of the cerebrospinal fluid samples from patients with CFS was positive for BDV after PCR and southern hybridisation. The sequence was confirmed to be BDV by DNA sequence analysis. Two of the serum samples were weakly positive on IF. All controls were negative.

CONCLUSION : It is unlikely that BDV infection is the major cause of CFS but it may play a role in occasional patients who have been exposed.

PATTERNS OF IMMUNE DYSFUNCTION IN PATIENTS WITH CFS - L. HABETS, H. KNECHTEN, P.

BRAUN Praxenzentrum Biondelstr PZB, Aachen Germany

Immune dysfunction /dysregulation is the central finding in CFS even when aetiology is different. Besides the weLl known serological findings of IgG subclass deficiency, and viral reactivation markers the impact of lymphocyte subclass determination and their activation states on diagnosis of CFS remains controversial as pathological findings were sometimes unequivocall and the relevance was doubted.

In 60 patients with clinical findings and complaints attributed to CFS the following lymphocyte subsets and their activation markers were measured on a Becton-Dickinson Facscan: CD3, Bcells CD19, helper CD3+, CD4+, Suppressor CD3+, CD8+, NK, CD16+, CD56+, activated CD8 (cytotoxic) CD8 HLA-DR+, CD8+-CD38+, CD8+-CD28+, CD8-CD11b+.

According to the major pathological mover (e.g. allergy, viral reactivation, environmental toxicity, M. Gilbert or mixture of these) distinct patterns of immune dysregulation were seen. In allergy driven CFS hyperproliferative extended but balanced subsets with differing activation signs were seen. When viral reactivation was dominant dysbalanced, highly activated subsets were found.

Mostly however low suppressor cells with hypoactivation can be seen. In patients with signs of autoimmunity heavily dysbalanced overactivated immune situations are observed.

More comprehensive analysis of CD4 and CD8 subgroups and especially their activation states should lead to a better understanding of CFS immune- pathology and cristaiiyzation of those markers who are relevant for diagnosis and therapy control.

CO-TRIMOXAZOLE/TRIMETHOPRIM - ME CASES - D.M. JONES

Perth Road 176, Iford, Essex, United Kingdom

The specific objective of this study was to establish whether ME resulting after use of Co-Trimoxazoie/Trimethoprim differs from more heterogenous cases. 28 responses (27 female, 1 male) to an article on the antibiotic Septrin (generic name CO-TRIMOXAZOLE), published in Interaction 17, Autumn, 1994, indicate that these ME subjects link the aetiology or onset of their illness to the above drugs, prescribed for cystitis/bladder/kidney/UTI (in 2 cases for reflux problems), chest/throat/ear infections, bronchitis/pharyngitis, sinusitis, acne, and nervous delibility.

In 2 cases use of Septrin exacerbated an existing viral condition; in 6 instances Septrin was prescribed longterm ranging between 2-9 1/2 years and succeeded by Trimethoprim once. Reported adverse reactions include severe blisters/blotches/rashes, allergic reactions including collapse and anaphylactic shock, headaches, nausea/vomitting, malaise, joint or muscle, pains, cold sweats, weight/hair or toe nail loss, purple hands, black nails and swelling, apart from usual ME symptomatology.

In 3 cases Septrin ceased to work. 25 of these subjects provided the following additional questionnaire results : 24 females and 1 male had a diagnosis of ME between 1984 and 1995, 15 by consultants, in most cases after many tests. Additional diagnoses include chronic anaemia, SLE, vasculitis, ulcerative colitis and cancer. 7/25 (28 %) came from the healthcare and teaching professions or were students. Average age was 41.2 years (range 20-55, SD 9.6); average length of illness was 7 years (range 1-25, SD 5.5) and average current disability rating (Bell's scale) lay between 30-40, including 5 ratings of 20. In 11 cases a viral illness precipitated onset of ME, in others recurrent chest/throat/kidney/bladder infections; some experienced gradually deteriorating health. The average number of symptoms reported after ME onset was 44 (SD 12.2) and 10 before onset (SD 7.7). Compared to earlier MSc study results, the following symptoms reported after ME onset was 44 (SD 12.2) and 10 before onset (SD 7.7).

Compared to earlier MSc study results, the following symptoms were reported with increased frequency after ME onset; numbness/burning/tingling, blurred vision/sports in front of eyes, dry mouth/throat, congested/dripping nose, breathing problems, environmental sensitivities, low grade fever, heart palpitations and great hearing sensitivity. Before ME onset cystitis, thrush, abdominal pain, cough/bronchitis and menstrual problems occurred with increased frequency. 15 subjects reported one or more allergies and 5 were exposed to pesticides or chemicals; 10 reported Glandular Fever amongst previous infections and most listed recurrent infections, including cystitis, tonsillitis, ear/chest, URT and urinary infections. All were prescribed Septrin and/or Trimethoprim longterm or often frequently and most also had other antibiotics, especially penicillins. BCG, polio, tetanus and smallpox were the most frequently mentioned vaccines, tetanus causing adverse reactions in 5 cases.

CONCLUSION : most of these subjects now feel that Co-Trimoxazole and/or Trimethoprim played a significant role in the develoment of their ME. Problems experienced with these drugs were later identified as part of ME symptomatology. The symptoms profile in these subjects differs slightly from that of a larger heterogenous group studied; most marked are severe reactions to these drugs and fewer 'slow-onset' cases. Of the remaining 3 cases, one subject has developed metastatic breast cancer, being wheelchair-bound for 6 years, another required recent hospital treatment. Use of Co-Trimoxazoie was restricted for treatment of specific ailments in the UK as from 6.7.1995.

THE CHRONIC FATIGUE SYNDROME: CLINICAL, IMMUNOLOGICAL AND NEURO-IMAGING CORRELATIONS IN 200 PATIENTS -L. LAMBRECHT, M. TROCH, C. VAN DE WIELE, L. MACHTELINCKX, S. LAUWERS, G. HOFFMANN, 0. LEBON, R.A.

DIERCKX Outpatient Internal Medicine Clinic, University Hospital, Hellige Famille Hospital Gent, Centraai laboratorium Gent and Antwerp, University Hospital Brugmann, Belgium

Between January 1991 and May 1995, 200 consecutive patients who fulfilled the Center of Disease Control criteria of CFS have been observed at our outpatient clinic. The aim of the study was to reevaluate the examinations testing the involvement of the immunologic system and the brain.

All patients were examined by a standardized questionnaire on 30 symptoms and were scored on the Karnofsky Scale (KS) evaluating severity. of disease. Dosage of routine laboratory parameters, of serum angiotensin converting enzyme level, serologic tests for Epstein Barr, Herpes Simplex and Coxsackie B4, and lymphocyte phenotyping were performed. Chest X-ray, abdominal ultrasound examinations and rest-electrocardiographic studies were done as part of the standard protocol but seemed not contributory. Tc-99m HMPAO brain SPECT was performed in 113 patients using a dual-head camera. MRI and polysomnographic results were related to SPECT-scan findings.

SPECT lesions, mostly involving the left temporal lobe, were found in 1/4th of patients. KS was negatively correlated with significant brain SPECT anomalies. SPECT abnormalities were more frequent and occurred in higher number when compared to MRI. In patients with symptomatic sleep disorders, polysomnographic results showed no correlation with distribution nor with severity of SPECT-scan anomalities. The immunologic test showed changes in lymphocyte phenotyping. CD4+, CD8+, CD8+157-, CD8+157+, CD19+, NK = CD16 cells, CD8+/DR+ and CD8+ICD38+ activated T-celis were increased in respectively 14, 11, 10, 13, 8, 24, 9 and 41 % of cases and decreased in respectively 12, 3, 3, 2, 2, 3, 3 and 0 % of cases. CD4+/CD8+ ratio was increased in 4 % and lowered in 13 % of cases. Erythrocytary magnesium levels were increased in 5 % and decreased in 51 % of cases. KS seemed negatively correlated with CD8+/CD38+ associated T-cell percentage in lymphocyte phenotyping and with erythrocytary magnesiumlevels.

In general, the findings presented support the encephalomyeiitic hypothesis of CFS.

PRIMARY SLEEP DISORDERS IN THE CHRONIC FATIGUE SYNDROME - 0. LE BON (1), B. FISCHLER (2), G. HOFFMANN (1), K. DE MEIRLEIR (2), R. CLUYDTS (2)

1 Universite fibre de Bruxelles, Brugmann University Hospital, Belgium
2 Vrije Universitelt Brussel, Akademisch Ziekenhuls, Belgium

In order to study the prevalence of primary sleep disorders in the Chronic Fatigue Syndrome, 54 consecutive CFS outpatients (36 women and 18 men, mean age 36), fulfilling the CDC criteria, not selected on the basis of sleep complaints, were scrutinized on clinical grounds and recorded during two nights for all-night polysomnography.

The patients were prepared for the recordings between 10 p.m. and 11 p.m. and were allowed to retire when they wished to (Goodnight Time). They were awakened around 7 a.m., had they not arisen spontaneously (Good Morning Time). EEG, electrococulogram, submental and tibial electromyograms, and ECG were continuously recorded. Respiratory movements were monitored with a pneumatic device taped to the thorax and abdomen. Oral and nasal airflows were detected with thermistors at the nose and the mouth. Oxymetry was measured by a finger oxymeter, snoring with a microphone and leg movements with a tibial electrode. 6.3 % - 45.8 % of the patients presented with a Sleep Apnea syndrome (the range being a function of the index cut-off), 4.3 % of the patients, with a Periodic Limb Movements syndrome, 0 % with clinical narcolepsy and 0 %, with ldiopathic Hypersomnia. The relatively moderate indexes of sleep apneas encountered could not account for the CFS symptoms in most cases. Hence, between 11 % and 45 % of the patients show the coexistence of a primary sleep disorder associated with the CFS.

As this leaves at least 55 % of the cases (strict criterias for sleep apneas) and more likely 89 % (more realistic criteria) with no such alternate possible explanation for the fatigue, this study, which is part of a larger protocol, confirms the value and interest of the CFS diagnosis.

IPSAPIRONE INDUCED ACTH RELEASE - EVIDENCE FOR IMPAIRED ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS IN PATIENTS WITH CHRONIC FATIGUE SYNDROME -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: the selective 5HT1A receptor ligand ipsapirone (IPS) induces corticotropin (ACTH) secretion in humans. To explore 5HT1A receptor mediated hypothalamic-pituitary-adrenal (HPA) system, this study was undertaken.

METHODS : fourteen patients (six males and eight females) and fourteen healthy subjects were studied. Chronic fatigue syndrome patients fulfilled the Centre for Disease Control (CDC) criteria. Healthy subjects were carefully matched for age and gender. Female subjects were tested in the early follicular stage of the menstrual cycle. Subjects presenting following an overnight fast. For measurement of plasma ACTH blood samples were taken at 0 min and thereafter at +30, +60, +90, +120 and +180 min. Each subject received 0.3 mg/kg ipsapirone at 0 min. ACTH was measured by radioimmunoassay.

RESULTS : in comparison to controls basal ACTH values were lower for, CFS patients. (Control 21 ug/l, CFS 5 ug/l). lpsapirone significantly raised plasma ACTH in healthy controls compared with CFS. DACTH (maximum - baseline) = 14.8 ug/l vs 4.8 ug/l.

CONCLUSION : the results demonstrate attenuated ACTH response to selective 5HT1A receptor ligand ipsapirone reflecting impaired activation of HPA axis in patients with chronic fatigue syndrome.

DESIPRAMINE-INDUCED GROWTH HORMONE RELEASE IN CHRONIC FATIGUE SYNDROME: EVIDENCE FOR REDUCED A-ADRENORECEPTOR RESPONSIVENESS - 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: the blunted growth hormone response to a-adronergic agonist clonadine has been reported in depression. This study was undertaken to determine growth hormone response to another a-adronergic agonist desipramine in patients with chronic fatigue syndrome in an attempt to differentiate between these two conditions.

METHODS : fourteen patients meeting CDC criteria for CFS and fourteen age and sex matched healthy individuals were studied. Subjects presented at 9.00 am following an overnight fast. Baseline blood samples were taken at -15 min and 0 min and thereafter at +60, +90, +120 and +180 min. Desipramine, 1 mg/kg orally, was administered at 0 min. Blood samples were collected in lithium heparin bottles and growth hormone was measured using an 'in house' immunoradiometric assay. Change in growth hormone (DGH) was measured by subtracting the baseline GH level from the peak value after desipramine administration.

RESULTS: the overall GH levels rose in response to desipramine challenge. The response was significantly less in the CFS group (mean DGH = 3.26 mU/I; SD # 1.90) than in the comparison subjects (mean DGH = 7.33 mU/I; SD # 5.18), P = 0.013.

CONCLUSION : the GH response to desipramine is decreased in CFS patients compared to controls indicating a decreased responsiveness of postsynaptic a-adrenergic receptors as has been reported in depression where GH responses were measured in response to clomidine. These results support the idea that the same noradrenergic mechanisms are involved in the pathophysiology of depression and CFS.

MR IMAGING IN THE CLINICAL DIAGNOSIS OF CHRONIC FATIGUE SYNDROME (CFS) - E. PIZZIGALLO, D. RACCIATTI, A. BARBERIO, A. TARTARO (1), A. CARRIERO (1), L. BONOMO (1)

1 Institute of Radiology and Clinic of Infectious Disease, * G. D'Annunzio' University, Chiety, Italy

OBJECTIVE : the aim of this study was to determine if the MR brain scans contributed to the diagnosis and management of patients affected by CFS.

METHODS : 23 patients (16 F and 7 M; mean age : 31.2 and 38.7, respectively) with clinical and laboratory findings of CFS were studied prospectively with MR lmaging. All MR studies were performed at 1.5 Tesla. Multislice spin-echo (SE) T1-weighted images (T1 Wl), 5 mm slice thickness (TR : 500 ms; TE 15 ms) were obtained on sagittal and coronal planes. Proton density weighted images (PDWI) and SE T2-weighted images (T2 WI), 5 mm slice thickness (TR 2200 ms; TE 15-80 ms), were acquired on axial plane. All MR examination were reviewed by two blinded neuroradiologists (AT, AC). MR evidence of prominent Virchow-Robin perivascular spaces, at the base and vertex of the brain, was interpreted as "normal".

RESULTS : small foci, hyperintense both PDWI and T2 WI, were found in the white matter of only two patients (8.3 %). These abnormalities were aspecific and labeled as "UB0s".

CONCLUSION : we conclude that MR findings found in the brains of the patients affected by CFS are aspecific. Moreover, the presence of these abnormalities (UBOs) is not significantly associated with the disease.

"CHRONIC FATIGUE SYNDROME" AND/OR "SPASMOPHILIA" -H. RUBINSTEIN

Neurology (EMG) Consultant, Paris, France

In France, we know for a long time a chronic illness that includes many agonizing - but common - symptoms such as crippling muscular fatigue, muscular pain, loss of intellectual efficiency, anxiety, headaches, digestive and cardio-vascular spasms, sleep disorders and non-epileptic seizures. We call it "Spasmophilia" and referred to a disorder with a neuro-muscular hyperexcitability whose primary causes were to be found in metabolic disorders related to calcium, magnesium, phosphorus, potassium and others, involving either intake deficiency or perturbed membrane permeability.

In my opinion - shared with numerous french physicians - "Spasmophilia', like "CFS", is a specific syndrome and neither a kind of hysteria, nor an anxious neurosis, a nervous breakdown or an expression of stress. But like CFS, "Spasmophilia" may often be mis-diagnosed for psychotic depressions or anxiety neuroses.

Now that I am well aware of a possible viral etiology of CFS, I made a survey of the last 500 new patients who were refered to me - or who consulted directly - for what was supposed to be "spasmophilia". They were 213 women, 113 men; ages between 16 and 70, among them 4 to 5 are from 20 to 45 years old. All these patients received a standard documented evaluation : clinical, neuro-physiological and biological. The clinical and neurological examination included psychological tests for selected patients. The neuro-physiological tests included : EMG, EEG, Evoked potentials [among them cognitive potentials (P300)]. The biological tests included : hormonal and metabolic levels, immunoelectrophoresis and lymphocytes count (T4/T8). For some of the neuro-transmitters were dosed.

In my findings, 40 % of the cases I saw had mainly or only metabolic disorders, 25 % had mostly anxiety symptoms, 15 % were real secondary depressions, 10 % suffered from panic attacks, 2 % were psychotic or had a neurological disease (Multiple sclerosis, myasthenia gravis) and about 8 % may be classified as primary "CFS' with an authentic decline of immune defenses and high frequency of infections. I will discuss the characteristic features of these conditions (clinical, neurological and biological) and my therapeutic point of view.

HORMONES IN THE MANAGEMENT OF CHRONIC FATIGUE SYNDROME - R. VALLINGS

Auckland, New Zealand

During the past 12 years, the author has seen over 750 patients diagnosed as suffering from Chronic Fatigue Syndrome according to the CDC criteria. 80 % of these patients were female and it was evident that many of the women noticed that cyclical and major hormonal events in their lives have considerable impact on the progress of their illness.

In view of the fact that more women than men report CFS, it is possible that oestrogen plays a role in aetiology. Some of the treatments currently in vogue such as calcium channel blockers, antifungals, H2.antagonists and spironolactone have the effect of increasing oestradiol levels. It is hypothesised therefore that the sense of wellbeing anecdotally reported by patients on these drugs may be due to an oestrogenic effect.

Treatment to minimise cyclical effects and/or to provide hormone replacement will be discussed together with the effects of pregnancy and lactation during this illness. Suitable contraceptive options will also be considered.

SLEEP APNOEA PRESENTING AS CHRONIC FATIGUE SYNDROME - TREATMENT WITH SUPPLEMENTAL OXYGEN DURING SLEEP -- C.K. VESSELINOVA-JENKINS, N. FINER

The lister Hospital, Chelsea, London, U.K.

Sleep apnoea syndrome (SAS) is a common, but often unrecognised condition that has a population prevalence of 1 - 3 % (Stradling J.R., Thorax, 1995; 50 :683-9). Symptoms of SAS include insomnia and daytime somnolence, which also form part of the Chronic Fatigue Syndrome (CFS). Both syndromes may be associated with disturbances of hypothalamic-pituitary function. We report two patients presenting with symptoms of CFS who were shown to have SAS associated with significant nocturnal hypoxaemia. Oxyhaemoglobin saturation (HbSaO2) fell by 4 - 13 %. Both patients were treated with domicilliary supplemental low flow oxygen via nasal cannuiae given during the night (Deviibiiss oxygen concentrator) and showed significant objective and subjective improvement (HbSaO2 while on oxygen therapy remained within normal limits of 97 - 98 %).

We speculate that unrecognised hypoxia could contribute to the pathogenesis of CFS either by impairing oxidative metabolic processes such as phosphorylation and ATP production, or alternatively by altering neuro-endocrine rhythms. Alternatively muscle weakness, as a result of CFS, lcoliid lead to obstructive SAS by an inability to maintain the oropharyngeal airway at night. Patients with CFS who have specific features of daytime somnolence warrant investigation with a sleep study to diagnose SAS.

HLA-DR CLASS II ANTIGENS AND POST-VIRAL FATIGUE SYNDROME - H.J. WHELTON, T.J. SMITH, E.J. FITZGIBBON

National Diagnosfics Centre, BioResearch Ireland, and Department of Pharmacology, University College Galway, Ireland

Class II major histocompatibility complex (MHC) giycoproteins, encoded by the HLA-D locus are involved in the response of T cells to antigen. Recent genetic studies suggest that there may be an association of Post-Viral Fatigue Syndrome (PVFS) with particular HLA types. The aim of this study is to investigate the role of immunogenetic factors in susceptibility to and development of PVFS. The major specific goal is to determine if there is an association between certain HLA-D antigen types and PVFS, specifically HLA-DRB1. For this study, a group of 48 unrelated Irish individuals with clinically defined PVFS were analysed. Polymerase chain reaction (PCR) amplification of the second exon within the HLA-DRB1 gene was carried out using seven PCR primer sets.

These result in the differentiation of individuals into HLA-DR haplotypes. Restriction enzyme digestion of the PCR products was then carried out to further subdivide the genetic haplotypes of the individuals. The allele frequencies obtained were compared to a healthy British caucasian control population. Statistical significance was estimated using the Chi-squared test with Yates correction. The data is now being collated from this study and will be presented in poster form.

TREATMENT WITH PERNA CANALICULUS AND D-GLUCAN OF CFS PATIENTS: RESTORATION OF NK ACTIVITY AND IMPROVEMENT OF CLINICAL SYMPTOMS -  O. YUN, Y. OKUBO, K. TESHIGAWARA, A. UCHIDA

Radiation Biology Center, Kyoto University, Japan

Chronic fatigue syndrome (CFS) is characterized by persisting debilitating fatigue and neuropsychiatric abnormalities. No effective therapy has been established.

In the present study we investigated immunological functions in patients with CFS and evaluated the therapeutic efficacy of the New Zealand green-lipped mussel extract perinea canaliculus (seatone) and S-1,3-D-glucan of Basidiomycetes Schizophyllum commune Frie sizofiran.

Vast majority of CFS patients had depressed blood natural killer (NK) activity, especially against virus-infected targets, elevated serum interleukin 2 (IL-2) levels and increased spontaneous DNA synthesis of blood lymphocytes. While lysis of tumor targets by NK cells required protein tyrosine phosphorylation, NK-mediated lysis of virus-infected targets was independent on Ca influx. NK cells were not activated by IL-2, though they expressed normal levels of a and s-chain of IL-2 receptors, to, which IL-2 effectively bound. Stimulation with failed to transduce signals in NK cells of CFS patients. CFS patients received daily oral administration of perinea canaliculus or sizofiran.

After 4-8 weeks of the treatment the patients showed an improvement of NK activity, acquisition of IL-2 responsiveness, and normalization of spontaneous DNA synthesis of lymphocytes and serum IL-2 levels. Following these immunological improvement, approximately 80 % patients completely or partially recovered from debilitating fatigue, neuropsychologic complaints and other associated symptoms. There was a close association between the improvement of host immunity and clinical symptoms.

These results suggest that perinea canaliculus and sizofiran may be effective therapeutic agents for patients with CFS and suggest the involvement of NK cells in the clinical course of CFS.