Abstracts of Posters Presented at The Bi-Annual Research Conference of the American Association for Chronic Fatigue Syndrome (AACFS) October 10-11, 1998

The prevalence of fatigue and bodily pain in those with chronic sinusitis

Author: Alexander C Chester

Objective: Recent rhinological reports have noted a high prevalence of significant chronic fatigue and bodily pain in individuals presenting with chronic sinusitis. Diminished social functioning, and limitations on physical activities also were noted more commonly in sinusitis patients. The general functioning of this group was below that of patients with congestive heart failure, angina, chronic obstructive pulmonary disease, and back pain. The following study was designed as an attempt to confirm the findings linking chronic sinusitis with both fatigue and bodily pain in a general internal medicine practice.

Methods: All 297 consecutive outpatients under the age of forty presenting to a single general medical practice for a comprehensive examination were interviewed after obtaining consent. Laboratory data included:complete blood count, erythrocyte sedimentation rate (Wintrobe method), standard 20 channel chemical analysis (SMAC), rapid plasma reagent serology, and urinalysis. For those over the age of 30, a chest roentgenogram was obtained. Symptoms recorded as present for this study must be both frequent and problematic (e.g., those with "bodily pain" had this symptom both frequently and severely enough to be troublesome). Chronic sinusitis was defined as any or all of the following chronic symptoms: facial pressure, cheek pressure, or frontal headache. Chronic unexplained fatigue was defined as fatigue for greater than one month that eludes explanation after the history, physical, and baseline laboratory tests were reviewed. Those with fatigue considered a normal response to excessive physical or mental demands, as well as mild fatigue, defined as that causing no significant impact on their sense of well being, were not considered "fatigued" for the purposes of this study.

Results: Of the 297 patients, 85 relayed a history of chronic sinusitis. When the 85 (study population) were compared to the remainder (control) there were no significant differences in physical or laboratory findings. Age, marital history, prevalence of depression, exercise patterns, and alcohol consumption were similar.
Fatigue & Chronic Sinusitis -- No. (%) 
Characteristic Study Control P value
Unexplained fatigue 46 (54) 21 (10) < 001
Daytime sleepiness 38 (45) 13 (6) < 001
Sudden onset of fatigue* 43 24 ns
Occuring after an URI*  26 10 ns
*Expressed as a percentage of those in each group with chronic fatigue (e.g., 43% of those with chronic fatigue in the study group had a sudden onset of that fatigue).
Bodilv Pain & Chronic Sinusitis No. (%)
Characteristic Study Control P value
Bodily pain  23 (27) 10 (5) < 001
Upper backache  14 (16) 10 (5) < 001
Fibromyalgia* 10 (12) 2 (1) < 001
*Refers only to point tenderness criteria for fibromyalgia.

Conclusion: Chronic sinusitis appears to be commonly associated with fatigue and body pain in the setting of a general internal medicine practice. This association raises the possibility that chronic sinusitis might also be related to other states of unexplained fatigue and/or bodily pain associated with upper respiratory symptoms: chronic fatigue syndrome, sick building syndrome, chemical sensitivity syndrome, Gulf War Syndrome, etc. A greater awareness and interest on the part of internists is needed to define the systemic symptoms of chronic sinusitis.

Prevalence And Overlap Of Chronic Fatigue Syndrome and Fibromyalgia Syndrome Among 100 Patients with Multiple Chemical Sensitivity

Authors: Albert Donnay and Grace Ziem

Objective: To determine the prevalence and overlap of chronic fatigue syndrome (CFS) and fibromyalgia syndrome ~MS) among adults diagnosed with multiple chemical sensitivity (MCS).

Methods: One hundred new adult patients (68F and 32M) with MCS, diagnosed by history, in a private practice from January 1996 through January 1998 were evaluated upon their initial visit for CFS and FMS using diagnostic criteria of the US Center for Disease Control (1994) and the American College of Rheumatology (1990), respectively. Data were recorded on the number of criteria met for CFS and the number of FMS pressure points demonstrating pain upon manual palpation. MCS was defined simply by multiple chronic symptoms in multiple organs triggered by multiple chemicals at or below previously tolerated levels of exposure and associated with a variety of immune, neurological and other abnormalities, as previously reported by Ziem and McTamney (1997).

Results: Of the 100 MCS patients, 88% met the criteria for CFS with all the major and an average of 6.4 of the 8 minor criteria, and 49% met the criteria for FMS with pain in an average of 15.2 of the 18 pressure points. In comparison, the 12% of MCS cases who did not meet the definition of CFS reported an average 1.75 minor criteria, while the 51% who did not meet the definition of FMS reported an average 3.26 painful pressure points. Unexpectedly, the prevalence of CFS was slightly higher among men (91% v.87%), but FMS was more than twice as common among women (59% v.28%). Among women, 56% met criteria for all three disorders, and an additional 31% had both MCS and CFS. This pattern was reversed in men, with only 28% having all three, and 63% having both MCS and CFS. The diagnosis of MCS alone was relatively rare, occurring in only 10% of women and 9% of men. Even rarer was the overlap of MCS and FMS without any CFS, which was found in just 2 women and no men. While FMS was almost always accompanied by CFS (n 100% of male FMS cases and 95% of female), CFS was associated with FMS in only 31% of the male CFS cases and 65% of the female.

Conclusion: MCS seldom occurs alone. In this study of 100 adults evaluated with MCS, almost all met current diagnostic criteria for CFS and almost half also had FMS, including the majority of women but less than a third of the men. This gender difference was due entirely to FMS, which was twice as prevalent in women as men. Nevertheless, this is significantly more men than found in studies of FMS among CFS clinic patients -- such as that by Buchwald et al (1994)--in which women with FMS outnumbered men by 3 to 1, and FMS among the general population--such as that by Wolfe et al (1995)--in which this ratio was almost 7 to 1. Also never before reported is the marginally higher prevalence of CFS found among men. The finding that only 53% of those with CFS also had FMS is significantly lower than that reported in several other studies, while the 96% rate of CFS among those with FMS is much higher than previous studies of FMS populations in which approximately 50% met criteria for CFS (Buchwald et al 1987; Hudson et al 192). The overall overlaps we found between MCS-CFS and MCS-FMS are 20% greater and less, respectively, than the 69% reported for both by Buchwald and Garrity (1994), but the MCS-FMS overlap is just 6% < the 55% rate of MCS found among FMS patients by Slotkoff, Radulovic and Clauw (1997). These extensive 2- and 3-way overlaps highlight the need for physicians to screen suspected cases of CFS, FMS and MCS for all three disorders using published criteria and to report results in these terms. We strongly recommend this be made standard practice in both clinical settings and research protocols. To improve early detection, treatment and prevention, further studies are needed to determine the relative order in which the hallmark symptoms of chronic fatigue, chemical sensitivity, and fibromyalgia evolve in these overlapping cases, as well as the kinds of events (illness, injury, toxic exposure, etc.) associated with the onset of these symptoms. We present a questionnaire developed for this purpose and discuss its use in the clinical evaluation of new CFS, FMS and MCS patients.
 

Descriptive data on patients with Chronic Fatigue Syndrome and chronic fatigue

Authors: Evengârd B, Lindh G, Jonzon E, Sandberg A, Theorell T.
Infectious Disease, Karolinska Institutet at Huddinge University Hospital and at Institute of Psychosocial Environment, Stockholm, Sweden.

Background: As part of a multi-disciplinary effort to find causative and/or influencing factors to Chronic fatigue syndrome, a patient population attending a university hospital-based CFS-polyclinic was characterized using questionnaires describing demographic and functional data, as well as coping strategies. The results were compared with patients with chronic fatigue to establish whether a difference exists between CFS and CF -- making CFS an entity.

Material: 239 consecutive patients fulfilling CDC-criteria for CFS, and 144 consecutive patients with CF attending a CFS-polyclinic in Stockholm responded to questionnaires including Wessely fatigue scale, Sense of Coherence (SOC), FIQ (Fibrositis impact questionnaire) and CPRS-S-A (depression scale) and NEPO (100 symptoms during the last 14 days). A follow-up after 3 years was performed as to fatigue scale and FIQ. For statistical analysis Chi-2 and One-way ANOVA have been used (SPSS 8.0).

Results:
  CFS  follow-up CF 
    n=25   
SEX*:       
women  68%   32%
men  42%   58%
age (average)  38 years   40 years
duration of illness* 3.9 years   5.0 years
infectious onset***  76%   59%
Fatigue scale  57 47 54
FIQ 52 45  47
SOC¹:  139   137
¹ (normal 140-160 p)      
       
CPRS-S-A (< 6)       
depression  7.7 SD4.0   7.4 SD4.7
compulsion  6.5 SD3.8   7.4 SD4.7
anxiety  8.2 SD3.4   7.5 SD4.1
NEPÖ  51.2   45.8

Conclusion: In the CFS group, there are more women as compared to the CF group, and the CF patients have a longer duration before coming to the polyclinic. More patients in the CFS group report an infectious onset. As to functional capacity, sense of coherence, and depression, there are no differences between the groups, nor in the number of symptoms reported. After three years the CFS patients report a decrease in fatigue and in functional capacity. More follow-up data will be presented.

Measuring Phases of Recovery in Patients with CFS

Authors: Patricia A. Fennell, Leonard A. Jason, and Susan M. Klein

Objective: In order to validly understand the relationship between stress, fatigue and activity it is critically important to understand the phase that a patient with Chronic Fatigue Syndrome (CFS) is in. If individuals are assessed when they are in different phases, this will complicate interpretation of findings, and is perhaps one of the reasons that there are so many inconsistencies within the CFS research literature.

Method: Recently, a four phase model has been developed by Fennell (1993). In brief, this model postulates that individuals with CFS progress through a series of phases. Phase I, the crisis phase, begins with the onset of the CFS illness. During this phase, patients feel that treatment is urgent. They have a low tolerance for ambiguity, and they feel responsible for the illness, yet have an externalized locus of control. They are generally preoccupied with thoughts pertaining to CFS, or they are in denial that they are actually suffering from the illness. During Phase II, the stabilization phase, patients recognize their symptom patterns and begin to feel some returning control over their lives. During this process, they seek alternative sources of support and treatment. They have a low tolerance for the chronicity of the illness, and continue to have a low tolerance for ambiguity. During Phase III, the existential conflict phase, patients have an increased internalized locus of control and an increased tolerance for ambiguity and chronicity. Patients become more aware of societal effects, and they begin to show compassion for themselves as they come to accept the complete loss of the pre-illness self and grieve deeply. From this grieving process comes the creative construction of meaning of their illness experience. In Phase IV, integration, individuals with CFS have successfully blended their pre and post crisis lives. They reconstruct a definition of themselves, form new friendships and rebuild former relationships. They express appreciation for themselves for having weathered the CFS experience and are finally able to accept the ambiguities of a relapsing and remitting illness.

Results: A questionnaire has been developed to tap these four phases, and it has been administered to several groups of people with CFS. Findings from this new instrument with several samples will be presented during this symposium.

Conclusion: Individuals perceive stress and cope with the illness experience differently, depending on which phase of the illness they are in. These findings have important implications for how we understand the relationships between stress, fatigue, and activity.

What do doctors and health workers of northeast Brazil know and do about Chronic Fatigue Syndrome?

Authors: Luis C Nacul, Fabio LR Pereira, Georgia A Jaques, Anaisa G Rarnos, Clineu JA Rodrigues, Isabel B Oliva, Nadja R Gonçalves, Roberta C Almeida
Universidade de Pernambuco, Faculdade de Ciências Médicas, Departamento de Medicina Social. Rua Arnóbio Marques 310, Recife-PE, 50100-130, Brasil.

Objectives:

a) To assess knowledge and practices of physicians of Recife, Northeast Brazil, in respect to chronic fatigue syndrome (CFS).
b) To assess beliefs and perceptions of community health workers (CHWs) on severe fatigue.
Methods: Data were separately obtained from physicians and CHWs. A questionnaire survey was directed to a random sample of 72 doctors working in teaching hospitals (55), and in primary health care (PHC) (17). A form containing 30 questions (mostly open), assessed their capacity of recognizing a clinical case of typical CFS, their knowledge/beliefs about diagnostic criteria, risk factors, treatment and prognosis, and their experience in diagnosing and treating patients with severe fatigue and CFS. A focus group discussion conducted with 7 CHWs explored lay-people's denominations of severe fatigue, and the CHWs perceptions on its causes and treatment. In a further stage of the research, we are currently conducting a community-based prevalence study of fatigue, chronic fatigue and CFS, in a district of Recife with a population of around 300,000 people.

Results: When prompted with a typical case history of CFS, 25 (34.7%) physicians mentioned CFS, either as the only diagnosis (5.6%) or as one of two or more possible diagnoses (29.5%). Hospital doctors gave the right diagnosis more frequently than those working in PHC (odds ratio=9.4; p=0.0l). A correct diagnosis was not associated with either time since medical graduation, or level of specialization. Personal and family problems (23.9%), "stress" (21.1%) and viral infections (19.7%) were the most frequently mentioned risk factors believed to be related to CFS. Psychotherapy (25.3%) and antidepressants (22.5%) were the most often proposed treatments. The prognosis is considered good by 65.9%. Based on doctors' experience, the median prevalence of fatigue and prolonged fatigue were estimated as 18.5% and 3.5%, respectively. CFS was considered a rare disorder, which has only been diagnosed by 20 (27.8%) of the doctors. The estimated prevalence of severe and prolonged fatigue was 0.2%. A typical CFS patient, according to doctors who have ever made this diagnosis, is a female (95.4%), young adult (87%), housewife (41.7%) with a low socio-economic background (57.1%). Only 1 doctor (1.4%) knew the diagnostic criteria. CHWs perceive severe fatigue as frequently related to "stress," other psychological problems, and to adverse life situations. Tuberculosis and infections due to unknown organisms could also explain some cases. CHWs believe that emotional support and good nutrition, possibly with vitamins supplementation, favour recovery.

Conclusions: CFS is an uncommon diagnosis in Recife, but its prevalence is possibly similar to that found in developed countries. Most doctors, especially those working in PHC, are unable to recognise a case of CFS and do not know the diagnostic criteria. Cases are believed to be often associated with psychological factors, especially "stress." Treatment emphasizes psychological support and the use of antidepressants.

Clinical and pathogenetical characterization of > 200 patients of an Italian Center for CFS Study

Authors: D. Racciatti, A. Barberio, I. Vecchiet, E. Pizzigallo
Clinic of Infectious Diseases, "G. D'Annunzio" University of Chieti, (Italy).

Objective: CFS probably is an heterogeneous disease, maybe multifactorial, or it includes different pathologies which manifest with the same symptoms. In some cases the mode of presentation of the illness implicate the exposure to chemical and/or food toxins as precipitating factors (e.g.: ciguatera poisoning, Gulf War Syndrome, etc.). In other CFS cases, the etiology is still unknown. There are various hypotheses that consider a possible involvement of multiple events in CFS onset where different precipitating factors can interact each other, even if not always all present in the single patient: latent and/or chronic viral infections, immunologic and neuroendocrine dysfiinctions, psychological, environmental and mood factors. According to this theory, we examined a consecutive sample of patients complaining of severe and chronic fatigue to assess the pathogenetic events and consecutively the appropriate therapeutic strategies for each patient.

Methods: The Clinic of Infectious Diseases of "G. D'Annunzio" University of Chieti is one of the main National Reference Centers for the CFS Study in Italy. From January 1992 to January 1998, 238 patients came to our observation: 110 of them met CDC criteria for CFS (1994), 105 did not; the other 23 patients are still under evaluation. All patients received a physical examination (including tests searching for the possible coexistence of a fibromyalgia syndrome), a psychiatric interview with several neuropsychological tests, laboratory tests (including magnesium determination on serum, and lymphocyte subsets characterization), neuroendocrine evaluation (circadian-rhythm of several hormones, buspirone challenge test), brain SPECT to assess the cerebral perfiision, and other examinations where necessary, according to the symptomatology reported by each patient (e.g. electromyographic, MR imaging, etc.).

Results: According to the preliminary results obtained from the various investigations, we subdivided our patients into different subgroups on the basis of pathogenetic events and clinical characteristics. We studied them in a comparative way to search for selective features that may allow a better characterization of each subgroup. We report the more significant data collected from this evaluation for a better understanding of the syndrome, and in particular, of its pathways in order to choose appropriate therapies for each subgroup.
 

Conclusion: CFS probably is an heterogeneous illness where different pathogenetic mechanisms may be implicated. So, on the basis of the relative pathways and clinico-pathological features, a classification of CFS patients into different subgroups should be considered for a better setting of each patient in order to evaluate a more appropriate therapy for each case.

Measuring outcomes of treatment in Chronic Fatigue Syndrome: a comparison of simple questioning vs. use of a validated outcome instrument (short-form 36)

Authors: Stanlev N. Schwartz MD, FACP, FIDSA; Rick Jones, PhD.
University of Oklahoma College of Medicine-Tulsa and Laureate Psychiatric Clinic and Hospital, Tulsa, OK

Objective: We hypothesized that assessing benefit of treatment of chronic fatigue syndrome (CFS) based solely on a patient's perception of improvement or decline ("I am better", "I am worse") might not provide a reliable measurement of outcome.

Methods: We performed Short Form 36 (SF36) tests (Medical Outcomes Trust) at time zero of treatment and again after approximately one year on 85 patients who met the 1994 CFS diagnostic criteria. No unique or standard treatment was used. Each patient was also asked a single self-report question (SRQ) after a year of treatment: "are you unchanged, better, much better, worse or much worse?". Each possible SRQ result was assigned a numerical value ranging from -2 for "much worse" to +2 for "much better." We compared the SRQ responses to each individual SF36 subscale and the summary SF36 scales at both time zero and time one year as well as to the changes in each scale over one year.

Results: We obtained SRQ data from 45 of the original 85 patients. Of the 45 patients, 15 reported improvement (10 "better," 5 "much better"), 11 reported worsening (7 "worse," 4 "much worse") and 19 reported no change. We found no correlation between the results of the SRQ and the physical component summary scales or the mental component summary scales. We found a positive correlation between the SRQ and the SF36 Vitality Transformed Score at one year (coefficient of correlation 0.339, p < 0.05). When analyzing improved and worsened patients separately, we could find no correlation between the direction of the SRQ result and changes in any individual SF36 subscale. Patients who reported improvement did not consistently show improvement in any of the individual scales or the summary scales. Similarly, a worsening SRQ did not correlate with negative changes on any of the subscales or summary scales.

Conclusions: Determining a benefit of therapy may be complex in patients with CFS. A simple "better-worse" query does not accurately or adequately reflect changes in physical and mental functioning as measured by a validated outcome instrument. Given that the severity of CFS is self-reported, we believe that clinicians, and especially investigators, should use validated outcome instruments such as the SF36 to determine the benefit and impact of treatment. The lack of appropriate outcomes measurement may be one reason why certain CFS treatments have appeared to yield different results in the hands of different investigators.

Do the 1988 and 1994 CFS case definitions identify the same illness complex?

Authors: Lana A. Tierskv, Stacy Weisberg, John DeLuca, and Benjamin H. Natelson

Objective: The decision to modify the original CFS case definition was based more on a perceived need to do so than on empirical data to support the proposition that the 1988 CFS case definition did not identify a distinct group of cases. If it is true that the 1988 criteria do not delineate a distinct group of cases, patients fulfilling these criteria should have the same symptom complexes as those fulfilling the relaxed 1994 case definition. Conversely, if patients fulfilling the 1988 case definition are a distinct group, their symptom pattern should differ from the profile of individuals fulfilling the 1994 CFS case definition. One purpose of this study was to evaluate these possibilities by comparing the symptom presentation of subjects diagnosed according to the 1988 CFS diagnostic criteria to the symptom complexes of subjects diagnosed according to the 1994 CFS diagnostic criteria. Differences in activity reduction and symptom onset were also investigated.

Methods: Sixty-two subjects completed a questionnaire that obtained information pertaining to CFS symptomatology as well as illness course. The data collection format of the list allowed subjects to respond if a CFS symptom was present as well as at what severity the symptom was experienced. Based on responses to the questionnaire CFS subjects were divided into two groups:

1) Subjects meeting the 1988 criteria for CFS, and
2) Subjects meeting the 1994 criteria.
Patients meeting the 1988 criteria also all met the 1994 criteria; however none of the patients meeting the 1994 criteria also met the 1988 standards. Thus, we were able to delineate two groups.

Results: When subjects who met the 1988 case criteria (n=45) were compared to those who met only the 1994 criteria (n=17), subjects in the 1988 group were found to suffer from a more severe form of the illness. Specifically, subjects in the 1988 group demonstrated more severe symptoms as well as a greater reduction in activity. The latter group also more frequently reported infectious-type symptoms as well as a sudden illness onset.

Conclusions: The 1988 and 1994 CFS case definition criteria appear to identify distinct patient groups. Given that the subjects in the 1988 group more frequently endorsed infectious symptoms as well as more frequently reported a sudden flu-like illness onset, an infectious etiology for this group is hypothesized.

Chronic Fatigue Syndrome: a nursing perspective

Chronic Fatigue Syndrome (CFS) is a illness of uncertain etiology which is estimated to affect a large proportion of the U.S. population (Demitrack & Abbey, 1996). A CDC clinic-based study using surveillance data from four sites estimated the point prevalence of CFS to be 4.6-11.3 cases per 100,000 population (Gunn et ai.; 1993). A more recent population-based survey in San Francisco suggests that the prevalence may be a high as 0.2% of the total population (Steele et al., 1996). Because CFS has no biologic marker, medical practitioners must rely on the patient's accurate description of psychological and physical symptoms in order to pursue a diagnosis. The recovery rate of most patient's afflicted with CFS varies. Longer duration of illness seems to be correlated with poorer prognosis.

In this study, I undertook a survey to determine the outcomes of patients seen and treated in our CFS clinic. The purpose of this study was to determine which treatments and activities correlated best with a good outcome. Because of the enormous cost incurred while "looking for a diagnosis", the financial impact on the patient and the public is substantial. Even after the diagnosis is made, costs continue to mount since many patients find that their functional capacity is completely depleted in the process. This raises the question of disability. Does disability help patients recover or not? Our study suggests that contrary to popular belief, patients recover from CFS whether they are receiving disability or not.

Methods: The subjects were selected randomly from a list of patients who were evaluated for another study and found to meet CDC/NIH criteria for CFS. Subjects were contacted and administered a brief, structured interview over the telephone. Those who could not be contacted on the first phonecall, were not recontacted. Those who were available were asked to respond to a standardized interview. Information on the individual characteristics and activities of each patient and their own assessment of their health were recorded. All patients were asked whether they were better, worse, or the same since their initial clinical visit. The patient's health self-rating was an estimate on a scale from 1 to 10 of their current symptoms (1 = profoundly symptomatic and 10= asymptomatic). Median health ratings in different groups of patients were compared for significance using the Mann-Whitney U test.

Results: Forty patients were contacted by telephone. All forty patients agreed to be interviewed a mean of 14.5 months (S.D. = 7.25 mos.; range = 2 to 36 months) after their first clinic visits. There were 38 females and two males in this group. One subject was pregnant. The mean age of the subjects was 41 years (range 20 to 63 years).

The subject's state of health, activity levels, treatments, and responses to treatments are summarized in the attached tables. The distribution of subjects according to their health rating is shown in Figure 1. In this figure, subjects fell into two clusters, one with health ratings > 4.5 (Group A), the other with ratings < 3 (Group B). This separation of patients according to symptom severity is consistent with the previously reported finding by Hickie and co-workers that patients defined by the current CFS case definition constitute at least two major groups with respect to symptom range and severity (Hickey et al., 1995). In the current study, these two groups were compared with respect to several other criteria, including age, exercise, activity (work vs. Disability), sleep habits and duration, medications (allopathic and alternative), weight gain or loss, and their perception of the cause (s) of their illness. The two groups were not distinguishable by any of these criteria. Comparisons of subjects' health rating based on some of these variables are depicted in attached figures 2-5.

Conclusion:

Is CFS/FM due to an undefined hypercoagulable state brought on by immune activation of coagulation? Does adding anticoagulant therapy improve CSF/FM patient symptoms?

Authors: D. Berg, L.H. Berg, J. Couvaras

Chronic Fatigue Syndrome may be due to a hypercoagulable state induced by immune activation of the coagulation (IAC) system. Using new coagulation assays that identify low levels of coagulation activation, this study was designed to quantitate such changes in CF S/FM patients, if any.

Patient studies in habitual pregnancy loss have shown that immune activation of coagulation produces an intermediate fibrinogen molecule called Soluble Fibrin Monomer (SFM). Increased SFM causes the body to reflexively produce more fibrinogen, resulting in elevated fibrinogen and both increase blood viscosity. Additionally, platelets may become activated, adding a substrate surface for continued thrombin generation, converting fibrinogen into SFM. This IAC may be due to inflammatory processes, viruses, or acquired coagulation inhibitors (lupus anticoagulants, anti-Phospholipid antibodies, anti-Phosphatidyl-Serine antibodies), and exacerbated by hereditary coagulation defects. These defects include Protein C, Protein S, AT deficiencies, APC Resistance, and elevated Factor II, X or VIII, which allow activation without the necessary control mechanisms to easily shut the hypercoagulable state down. Most patients with increased fibrinogen and SFM levels also have activated platelets and a faster RATE of clotting knetics (Sonoclot). These four screening tests define immune activation of coagulation.

Applying the sarne principles of IAC to CFS, a pilot study of 20 patients with rheumatology-defined CFS/ fibromyalgia was begun to see if these activation markers were elevated as in habitual pregnancy loss. In this study, there was a high correlation of abnormal test values in the four screening tests (fibrinogen, SFM, PA Score & Sonoclot Rate).
TESTS: Abn # / Total #  %Abnormal
Sonoclot rate 18/20 90%
Soluble Fibrin Monomer  14/16 88%
Fibrinogen  9/19 48%
PA Score (Platelet Activation)  12/20 60%
The high percentages of increased SFM and the Sonoclot rate elevation, with moderate increase in fibrinogen levels (mean average: 326 mg/dl - Ref Range: 180-310 mg/dl), indicates activation of coagulation in these patients. In addition, 60% of patients also had platelet activation.

16 patients with defined CFS or FM, who had positive baseline studies, were then treated with placebo saline injections BID and an oral placebo (if PA Score was elevated) for one week, followed by anticoagulant therapy of standard heparin, SQ 5000-8000 units BID. Patients with platelet activation were also given 81 mgs ASA daily. The four coagulation tests were repeated weekly. Dose adjustments were made, if needed, to decrease SFM and PA scores and maintain the patient in the normal range. Heparin therapy was given for one month. Patients were then rated on their subjective responses in their improvement to headache, fatigue and pain: no improvement, some, moderate, or significant improvement.
GROUP:  # Patients  Response  None  Some  Moderate  Significant 
Fibromyalgia  7   0 1 3 3
CFS  9   0 0 4 5

9 patients were then converted to 1.0-2.5 mgs coumadin daily. The patients were then maintained on low dose cournadin, some for up to a year. There appears to be significant improvement of patients using anticoagulant medications.

Most patients reported feeling like their old selves within 48-96 hours of heparin therapy with increased energy levels. This suggests that these medications are acting on the hypercoagulable state by simply shutting down the thrombin generation, resulting in a decrease of blood viscosity as SFM is removed from the circulation and the fibrinogen level begins to return to normal. This is intriguing evidence of a practical treatment to improve patients quality of life and decrease their major complaints and symptoms.

The final question is simply: As we age, do the endothelial cells lose their ability to produce enough heparans to maintain an anticoagulant environment and prevent inappropriate thrombin generation, leading to increased SFM levels and increased blood viscosity?

Growth hormone secretagogue therapy provides effective relief of most symptoms related to Chronic Fatigue Syndrome in a prospective patient centered outcome study

Authors: Paul R. Chencv,MD., Ph.D., Holly Keever, LMT

Objective: Recent studies have linked low growth hormone levels as evidenced by low IGF- 1 levels to a subset of patients who meet criteria for Chronic Fatigue Syndrome (CFS). Therapy with growth hormone given daily for nine months showed significant improvement in over-all symptomatology. Given the potential concerns for growth hormone use as well as cost, we undertook a study using plant-derived, bioactive polypeptides with demonstrated ability to raise IQF-1 levels as a treatment modality in a prospective, patient centered outcome study on CFS.

Method: Fourteen patients who met the criteria for CFS were treated once a day for five days out of seven using a specially configured secretagogue with seven bio active polypeptides known to increase IGF-l levels in human subjects. Patient outcomes were assessed using a physician-assigned score of global response, as well as patient-defined outcomes using a clinical questionnaire validated against the MOS SF-36 short form. The patients were treated for ninety days, and IGF-l levels were drawn at baseline and at sixty days.

Results: A majority of patients, (8 of 14) or 57%, reported a beneficial response which ranged from fair to excellent as judged by both physician and patient scoring systems, with an average drop of 35% (range 21% to 59%) in patient symptom scores as measured by a self-report multiple symptom questionnaire. The symptoms which were the most responsive to this therapy were fatigue and muscle pain, but the symptom improvement was notably broad based. Three out of eight responders termed their response excellent. Examination of the excellent responders demonstrated that they had significant deviation in their IGF-1 levels compared to the group as a whole, both higher than, and lower than, the other eleven patients. Most interesting was evidence that the bioactive polypeptide caused a "'normalization" of IGF-l, lowering it in cases in which it was elevated and raising it in cases in which it was low, especially in those who responded best to it. In this regard, secretagogue therapy appears to be "adaptogenic", and therefore may be a superior therapy from a safety standpoint compared with exogenous growth hormone.

Conclusion: Patients treated with bioactive polypeptides which act as growth hormone secretagogues was shown to significantly improve a majority of CFS patients as assessed by both physician and patient-derived outcome studies. The direction and degree of IGF-1 response appears to be independent of the clinical response, and there is evidence to suggest that the response is adaptogenic and capable of raising or lowering IGF-1 levels with clinical improvement in either case.

An overview of Ampligen and experience in a small cohort

Authors: Charles W. Lapp, M.D.*, Cynthia S. Voyles, A.N.P., M.S.N., Patricia Davis, C.M.A. and Sheila Langford, R.N.;
Duke University Medical School, Durham, North Carolina,* and Hunter-Hopkins Center, P.A., Charlotte, North Carolina, USA

Double-stranded RNA has been available for the treatment of viral infections for over 3 decades, but was considered too toxic for human use. The periodic inclusion of a uridine molecule in the strands, however, makes the molecule quite safe for human use. Poly(I):Poly(C12U), or Ampligen, has been shown to be both antiviral and immunomodulatory in human beings.

Initial studies have demonstrated considerable efficacy and safety in the treatment of chronic fatigue syndrome (CFS). An open-label study of Ampligen involving 15 subjects who met the 1988 CDC Criteria for CFS was begun in 1988. Over 24 weeks of therapy with Ampligen, general performance scores and cognition improved progressively, and HHV-6 reactivation was significantly reduced. Based on this pilot study, a randomized, placebo-controlled, double-blind, multicenter study of Ampligen was undertaken in 1989. Again, general performance and cognition improved as did activities of daily living and exercise treadmill performance. In 1997 the FDA approved the use of Ampligen in a limited number of desperately ill persons with CFS as part of a "fast track" drug program.

This presentation will briefly review the pharmacology of Ampligen and previous clinical trials. We will describe our experience treating five subjects in Charlotte with Ampligen over six to twelve months, including follow-up after discontinuation of therapy.

5 year follow-up of young people with Chronic Fatigue Syndrome following the double-blind randomised controlled intravenous gammaglobulin trial

Authors: Rowe, K.S., Department of Paediatrics, Royal Children's Hospital, Vic.

INTRODUCTION: Eighty-nine of ninety-one young people with Chronic Fatigue Syndrome completed a double-blind randomized controlled trial of intravenous gammaglobulin. This study demonstrated a significant difference between the baseline functional score and 6-month followup for both groups, and between the mean functional outcomes for both treatment groups at 6 months. For the young people who were categorized as anergic (no response) (24%) using the CMI Multitest, or hypoergic (response less than 2-9 mm in total) (33%), there was a significant difference (p < 0.0l) between treatment with gammaglobulin and placebo on functional outcome. There was no difference between placebo and gammaglobulin in improvement rate for those with normal cell mediated immunity as measured by the CMI Multitest. A three and five year follow study of young people has been conducted to determine whether the improvement following the intravenous gammaglobulin was sustained.

Methods: Initial telephone contact and a questionnaire that assessed functional outcomes including physical activity, social activities, work/school attendance and work/school workload was used. Strategies and treatment that were found helpful, and ways to improve management, were also asked. Delayed-type skin hypersensitivity reaction was measured (using CMI Multitest) in those who were anergic in the initial study.

Results: Follow-up data were obtained on 86 of 89 after the study concluded. The 3-year follow-up yielded a 75% response to the questionnaire. A 78% follow-up response at 5 years was achieved for those enrolled in the study with 84% (n=74) of those who completed the study being traced. The mean follow-up time from commencement of illness was 56 months (sd 25 months, range 15-112 months). There was no persistent deterioration in function related to CFS in any young person. Four had reported recurrence of symptoms lasting 3-8 months, and again improved. Others remained "improved" or continued to improve. Seventeen percent of those who responded were still moderately unwell, with another 23% "not back to normal yet". Sixty percent of participants considered they were "well" at the last follow-up, with 43% scoring 10/10. However, 59 of 86 (66% of the total) had scored 8 or above, from a maximum of 10, at some stage after the trial ended. Seventeen (20%) had another condition during or after their illness. Of those who had been well, 2 were pregnant, 1 had chronic myeloid leukemia and 3 had recurrent CFS. Of those who were currently well, 2 had diabetes, 1 had had severe depression, and 1 had endometriosis. Of those who had never been well since the onset of CFS, 4 had persisting psychiatric problems (depression, bulimia, and drug abuse), 3 had gynecological problems such as endometriosis or cystic ovaries, 1 had an exacerbation of CFS symptoms persisting for > 6 months. Delayed-type skin hypersensitivity reaction had remained hypoergic in 1/3 of those previously anergic but now "well". Anergy or hypoergy did not predict functional outcome at five years after the trial, although an earlier improvement was noted in those who were anergic and received gammaglobulin. There was no difference in perceptions of what was helpful or unhelpful in management between the group who received gammaglobulin and those who received placebo.

Conclusion: There was no deterioration in overall function over the 5 years following participation in the gammaglobulin trial, and young people continued to improve, although a significant number were still disabled. The significance of the abnormal delayed-type hypersensitivity reaction for the response to gammaglobulin is uncertain and warrants further investigation. There was no difference between the recovery rate for males and females.
 

Effective treatment for Fibromyalgia and Chronic Fatigue Syndrome: a placebo controlled study

Authors: J.E. Teitelbaum M.D.*¹, B Bird, M.T.,C.L.S *, R Greenfield, M.D.¹, A Weiss, M.D.¹, L Muenz, Ph.D², L Gould*³
*Annapolis Research Center For Effective FMS/CFIDS Therapies; 466 Forelands Rd., Annapolis, MD 21401;
¹ Anne Auundel Medical Center, Annapolis, MD;
² Gaithersburg, MD;
3USDA, Beltsville, MD

Objectives: Hypothalamic dysfunction has been suggested in Fibromyalgia (FMS) and Chronic Fatigue Syndrome (CFIDS). This may result in disordered sleep, subclinical hormonal deficiencies, immune dysfunction (with opportunistic bowel infections and associated nutritional deficiencies) and autonomic dysfunction (e.g., neurally-mediated hypotension [NMH]). Our previously published open trial showed that patients usually improve, often dramatically, by treating all the above processes simultaneously. Our current study re-explored this using a randomized, double-blind design with an intent-to-treat analysis.

Methods: 72 FMS patients (66 female; 6 male; Avg. age 44.6 years; 69 also met CFIDS criteria) received all active or all placebo therapies as a unified intervention. Patients were treated, as indicated by symptoms and/or lab testing, for: (1) subclinical thyroid, gonadal, and/or adrenal (Cortisol and DHEA) insufficiency, (2) disordered sleep (Zolpidem, Valerian/Melissa, Trazodone, Amitriptyline, Cyclobenzaprine, Carisoprodol and/or Clonazepam), (3) suspected NMH (Fludrocortisone), (4) opportunistic infections (e.g., parasites, Clostridia Dfficile, fungal overgrowth), and (5) suspected nutritional deficiencies (multivitamin, magnesium glycinate/malic acid, B12, and iron).

Results: 38 patients were in the active group and 34 patients in the placebo group. 32 patients in each group completed the study. At the final visit, in the active group, 16 were "much better", 13 "better", 2 "same', 0 "worse", and 1 "much worse" vs 3,9,11,6, and 3 in the placebo group (p < .0001, Mantel-Haenszel trend test). Significant improvement in the FMS Impact Questionnaire (FIQ) scores (decreasing from 54.8 to 33.2, vs 51.4 to 47.7: p < .0001, t-test), Analog scores (improving from 176.1 to 311.1 vs. 177.1 to 211.3, p < .0001), and Tender Point Index (TPI) (31.7 to 15.5 vs. 35.0 to 32.3, p < .0001) were seen.

Conclusions: Significantly greater benefit was seen in the active group than in the placebo group for all primary outcomes, confirming that effective treatment is now available for Fibromyalgia and Chronic Fatigue Syndrome.
 

The use of serine in the management of Chronic Fatigue Syndrome

Authors: Rosamund Vallings, M.B., B.S.

Objective:Urinary serine levels were checked and found to be low in most patients whose illness fitted the CDC criteria for a diagnosis of Chronic Fatigue Syndrome (CFS). A low serine level has previously been identified as a possible urinary marker previously known as CFSUM2 for CFS. The objective was to assess the value of serine supplementation in the management of CFS

Method:: Analysis of urinary metabolites was performed in 24 patients diagnosed as suffering from CFS. Serine supplementation was offered as a possible treatment option to those with low serine levels. 15 agreed to participate, and serine was prescribed in a dose of 500mg twice daily to these people. A metabolic screening questionnalre was administered prior to treatment and thereafter at monthly intervals.

Results: Serine levels were found to be low in all patients. All those wanting to use serine supplementation completed the initial screening questionnaire. Subset scores, the total score for each patient and group were calculated both in the preliminary screening and at each follow up. The results of the screening questionnaire and the outcome of the treatment will be presented and discussed.

Conclusion: This is a preliminary study undertaken in a general practice setting, and although there is considerable evidence from the results that these patients had benefit from serine supplementation, the study should be replicated using a double blind placebo controlled approach. It is hoped that follow up urinary serine levels will also be performed.

References:
Fukuda K, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Annals of Int Med, 1994, 121, 953-959
McGregor N.R, et al: Preliminary determination of a molecuar basis to chronic fatigue syndrome. Biochemical and Molecular Medicine, 1996, 57, 73-80
 

A case series survey of silicone breast implant patients

Authors: Cichon M. M.D., Farrell, D., Ganjo, S., Sadler, G.

Objective: To survey the symptoms of a large group of breast implant patients displaying illness, and to determine if any clinical or serological features predominate.

Method: A private internal medicine practice.

Results: A referred sample of 415 patients with fatigue of long duration, followed by muscle/joint pain, cognition problems, polyneuropathy, and localized breast pain.

Conclusion: Silicone adjuvant breast disease may be a novel disorder, possibly auto-immune, producing atypical syndromes that do not fit within the classic diagnostic criteria of known conditions. Furthermore, the diversity and distinction of silicone adjuvant breast disease may require the medical community to accept it as a new entity, encompassing a neurological and connective tissue disorder.

T-lymphocytes in CFS -- in vitro reaction to mutagens

Authors:: I. Hauspie¹, I.Campine²*, P. De Becker², K. De Meirleir², M. Kirsch-Volders¹
¹Department of Human Genetics, Free University of Brussels, Brussels, Belgium
²Department of Human Physiology, Free University of Brussels, Brussels, Belgium
* I. Carnpine is supported by funds from the Foundation for Scientific Research, Belgium (F.W.O.).

Objective: Many studies in CFS patients suggest a virally-triggered onset, associated with an abnormal immune function. With recent findings in mind concerning the role of viral proteins taking in cell proliferation control, our aim was to test in vitro cell proliferation in CFS patients and healthy controls, both in normal conditions and after treatment with different mutagens.

Methods: Human lymphocytes from 8 patients and 14 controls were cultured in the presence and absence of different mutagens. Using the cytokinesis blocked micronucleus assay, the proliferation index was assessed and chromosomal abberations were detected. We also examined the effect of ethanol exposure on T-lymphocytes in vitro.

Results: The results show that the proliferation index in CFS patients (in absence of a mutagen) is slightly lower than in controls, but CFS patients show more spontaneous damage during cell division than controls. In the absence of S9, the cell division is reduced in the presence of ethanol in CFS patients. Ethanol also induces damage in dividing T-lymphocytes in CFS patients in the absence of S9. Finally, lymphocytes of CFS patients seem to be more resistant to in vitro treatment with MMS than controls.

Conclusion: These results add information to the existing knowledge of intracellular abnormalities in CFS. Our findings point toward abnormalities in intracellular protein metabolism, and increased sensitivity to alcohol. We also postulate, from the MMS experience, that lymphocyte cell membrane permeability is altered.

Markers of immune activation are associated with psychological distress in patients with CFS

Authors: Lynn Helder. Ph.D., Stacy Wagner, M.S., Robert Keller, M.D., Nancy Klimas, M.D. and Michael Antoni, Ph.D.

Objective: Chronic immune activation, as suggested by abnormal T-cell phenotypes, and psychological distress have often been associated with Chronic Fatigue Syndrome (CFS), although conclusions remain controversial. Our purpose was to further explore the relationship between immune functioning and psychological distress in patients with CFS.

Methods: 25 subjects meeting the Centers for Disease Control criteria for CFS were examined prior to participation in a cognitive therapy intervention. Blood draws and psychological inventories were completed within two weeks prior to the group onset. Analysis of markers included activated T-cells (CD26+CD2+CD3+), T-helper cells (CD4+CD3+), T-suppressor/cytotoxic cells.(CD8+CD3+), and T4/T8 ratio (CD4/CD8). Subjects were also given the Profile of Mood States (POMS; with Anger, Anxiety, Depression, Confusion, Fatigue., and Vigor subscales), The Sickness Impact Profile (SIP; measuring psychosocial impairment), and the Attitudes Towards Self Scale (ATS; with Self-Criticism, Generalization, and High Standards factors).

Results: The POMS depression and anger subscales and the total POMS score were significantly correlated with the T4/T8 ratio (r = 44, p < .04, r = .50, p < .02; r = .44, p < .05, respectively). In addition, the POMS depression and anger subscales also showed a marginal inverse correlation with T-suppressor/cytotoxic cell percentage (r = .37, p < .09; r = -.40, p < .07, respectively). Similarly, the psychosocial impairment score of the SIP was also correlated with the T4/T8 ratio (r = .33, p < .09) and negatively associated with the percentage of T-suppressor/cytotoxic cells (r = -.36, p < .06). The Generalization factor of the ATS measuring the tendency to generalize negative events, was significantly correlated with activated T-cell numbers (r = .39, p < .04), T4-helper cell numbers (r =.37, p < .06), and T-helper cell percentages (r = .39, p < .05).

Conclusions: Our findings suggest that immune activation, as defined by elevated activated T-cells, T-helper cells, and T4/T8 ratios, is associated with measures of psychological distress and attitudes about oneself. The elevations in distress and impairment measures were also associated with a reduction in the percentage of T-suppressor/cytotoxic cells. There may be a subset of CFS patients exhibiting a depleted T-suppressor/cytotoxic cell population that tend to be more symptomatic and more emotionally distressed. Psychological distress may have a stronger relationship with immunologic functioning in those CFS patients who are the most ill, as suggested by increased activated T-cells, T-helper cells, and T4/T8 ratios, and a reduction in T-suppressor/cytotoxic percentages. Since the ATS was associated with immune activation, attitudes about oneself may mediate the association between psychological distress and decreased T-suppressor/cytotoxic cells. These findings are based on pilot data, and therefore, conclusions about whether or not the CFS subjects had significantly elevated T4/T8 ratios or abnormally low T-suppressor/cytotoxic percentages as compared to normal controls can not be made without further study.

Immunocytology and in vitro reverse-transcriptase activity in CFS

AuthorsM.I. Holmes, R. Easingwood, J. Cross, and J. Faed

Objective: This paper describes two blind clinical trials of paired, age, sex and ethnically matched patients with CFS; 24 pairs of patients and controls in the first, and 18 in the second. In the first, the range of duration of symptoms was 1 to 3.5 (mean 1.5) years and in the second 1 to 5 (mean 1.7) years. Peripheral blood lymphocyte (PBL) cultures were assayed in triplicate for reverse-tran scriptase (RT) activity, and examined by EM for the presence of virus-like structures at days 0 and 12 and CD2, 3, 4, 8, 16, 20, and 31, and B1 phenotypes were counted at day 0 by FACScan.

Methods: A single dose of 1 µg ml-¹Concanavilin A (Con A) was given to all cultures at day 0. At days 4, 8 and 10 they were given 4.5 ng ml-¹ human recombinant IL-2. Cells were harvested at day 12 for EM studies, and ultracentrifuged supernatants and cells for RT assay using a poly rA:oligo dT template-primer and measuring RT activity by uptake of tritiated thymidine triphosphate.

Results: In Trial 1, RT activity up to 3 times background was observed in 9, and virus-like structures in 7 of 24 patients, and not in controls. Group means showed a significant CD4 cytopenia. In Trial 2, RT activity at levels of 2 to 4 times background were observed in 5 patients, and virus-like structures were observed in 4 of these, and not in controls. Group means showed significantly reduced CD4/CD8 ratios and an NK cytopenia. RT activity and EM virus-like structures were seen almost exclusively in the cohort of patients who identified the onset of their condition with a non-specific, acute febrile illness and whose duration of symptoms was 2 years or less.

Conclusion: These studies suggest the in vitro RT activity and the presence of virus-like structures in PBLs may correlate in CFS with patients who relate the onset of their condition to a non-specific, acute febrile illness.

Lymph node morphology and phenotype in Chronic Fatigue Syndrome

Authors: Nancy Klimas, Kevin Maher, Roberto Patarca, Jean Walling, Mack Smith, and Mary Ann Fletcher. University of Miami School of Medicine and the Miami Veterans Affairs Medical Center, Miami, Florida.

Objective: Chronic Fatigue Syndrome is an illness which is associated with immune dysfunction, including abnormalities in the function and activation status of peripheral blood lymphocytes. There has been no study of the lymph node compartment in this illness.

Methods: Patients who had volunteered to undergo lymph node biopsy while participating in the pre-clinical phase and phase I studies of a novel immunomodulatory therapy were evaluated. At the time of this abstract 6 lymph nodes have been evaluated. An additional 9 will be studied prior to the October AACFS meeting.

Results: Of the 6 lymph nodes currently available for study, 1 is tonsillar, 2 posterior cervical, and three are axillary. Four demonstrated normal architecture and morphology. Two had a slight increase in the number of histiocytes. The tonsillar sample was, as expected, predominantly B-cells (56%). Excluding the tonsillar sample, the lymph nodes showed the following lymphocyte surface phenotype: The CD4 percent ranged from 61% to 83% (mean 70%), the CD8 percent from 8% to 19% (mean 11%) and B-cells (CD 19+) ranging from 13% to 30% (mean 20%). Few natural killer cells were present. CD56+CD3- lymphocytes ranged from 0.9% to 2.2%. The activation marker, CD26 was present on 63% to 77% of the CD2+ lymphocytes. Memory CD4 cells predominated with only 16% (range of 2% to 30%) expressing the naive subset marker, CD45RA. Not surprisingly, the majority of the CD4 cell population also expressed 62L (86%), which is considered to be a lymph node homing adhesion molecule. CD8 cells were predominantly CD38+ (95%) and DR negative.

Discussion: This initial study of the distribution of lymphocyte subsets in the lymph nodes from patients with CFS offers confirmation of our hypothesis regarding the immunopathogenesis of this syndrome. The data from the first 6 patients presented here indicates a preponderance of activated T-cells that is even higher than that reported in peripheral blood. The CD8 cells express the phenotype CD38+ and DR-, which is associated with cytotoxic T-cells. The ratio of memory to naive CD4 T-cells is skewed upward, as is the case in peripheral blood. These findings are compatible with a chronically activated immune status in this patient group.

Immunological response in Chronic Fatigue Syndrome (CFS) following a graded exercise test to exhaustion

Authors: J. LaManca, S. Sisto, J. Ottenweller, A. Peckerman, S. Cook, T. Denny, W. Gause and B.H. Natelson. NJ CFS Research Center, New Jersey Medical School, and VA NJ Health Care System, East Orange, NJ.

Objective: Data have indicated that CFS may involve abnormal immune system functioning. Exercise can be an useful tool in stimulating an immune response. This study was conducted to evaluate the immunological response of CFS patients to an exhaustive bout of exercise.

Methods: The two groups, which were matched for age, sex, and socioeconomic background, consisted of 19 CFS patients meeting the 1988 CDC criteria and 14 non-exercising (i.e. sedentary) controls respectively. All were females in the luteal phase of the menstrual cycle. Venipuncture was performed pre-, 4 minutes post-, 1 hour post-, and 24 hours post-exercise. The graded exercise test (GXT) consisted of walking on a treadmill with the work load increasing every 3 minutes to voluntary exhaustion. Expired gas was analyzed during the GXT. Peripheral blood cells were labeled with the following monoclonal antibody combinations: CD3/CD8, CD3/CD4, CD3/CDl9, and CD3/CD (16&56). The cytokines: IFN-gamma, IL-2, IL-4, IL-10, IL-12, and TNF-alpha were assayed utilizing a quantitative RT/PCR assay. White blood cells (WBC) and all subset concentrations were adjusted for plasma volume shifts.

Results: During the GXT no significant differences in VO2peak (28.6 ± 1.7 vs 30.8 ± 1.2 ml:kg-1min -1), HRpeak(175 ± 4 vs 183 ± 4 bpm) and RER (1.08 ± .02 vs 1.13 ± .02) were seen when comparing CFS to CON. The number of WBC, CD3+CD8+, CD3+CD4+, T-Cells, B-Cells, Natural Killer Cells, and IFN-gamma all were significantly changed across time (all comparisons, p < .0l). No significant group differences were seen for any of the immune variables. Also the changes across time were similar for both groups with the exception of IL-2, where a significant group-by-time interaction was seen (p < .03). Only one of the CFS patients had elevated blood lymphocyte levels 24 hours after the GXT.

Conclusion: The immune response of patients with CFS to a single bout of exhaustive exercise is not significantly different when compared to a group of sedentary healthy controls.

(This work was supported by NIH Center grant AI-32247)

Could nickel allergy be involved in the pathogenesis of Chronic Fatigue Syndrome?

Authors: J.A. Marcusson¹ , G. Lindh², B. Evengård²
¹Department of Dermatology, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden
²Division of Infectious Diseases of the Department of Immunology, Microbiology, Pathology and Infectious Diseases, Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden

Objective: Allergic reactions have been reported to occur more often in patients with CFS, and fatigue is also a common self-reported symptom among patients with allergy. The aim of this study was to study whether allergies to various metals might play a role in the pathogenesis of chronic fatigue syndrome.

Method: Fifty patients fulfilling the chronic fatigue syndrome (CFS) criteria according to CDC, and 73 sex and age-matched healthy controls without history of metal allergy or symptoms of fatigue, were percutaneously patch-tested with eight different metal salts. The following metal salts were used as test reagents: potassium dichromate, metallic mercury, cobalt chloride, nickel sulphate, gold sodium thiosulphate, palladium dichloride, tin and silver nitrate. Test reagents and test chambers were obtained from Chemotechnique Diagnostics AB, Malmö, Sweden. The test chambers were removed after 2 days and the skin reaction was graded after another 2 days as 0, 1+, 2+ and 3+ respectively. Only 2+ and 3+ reactions were accepted as true positive.

Result: Some type of contact allergy to tested metal salts was noted in 46% of the patients with CFS and in 36% of the healthy coritrols. Nickel sulphate allergy was significantly more common among the CFS patients, and this was even more noteworthy among the females. We found nickel allergy in 52% of the female CFS patients compared to 19% of the female control group (p < 0.05). No significant difference was found in skin reaction to the other metal salts tested in this study.

Conclusion:

Serum neopterin and somatization in women with chemical intolerance, depressives, and normals

Authors:Roberto Patarca, Nancy G. Klimas, Iris R. Bell, and Elizabeth Hardin
Department of Medicine, University of Miami School of Medicine, Miami, Florida, and
Department of Psychiatry, University of Arizona Health Sciences Center, Tucson, Arizona.

The symptom of intolerance to low levels of environmental chemicals (CI, chemical intolerance) is a feature of several polysymptomatic conditions that overlap symptomatically with depression and somatization, i.e., chronic fatigue syndrome, fibromyalgia, multiple chemical sensitivity, and Persian Gulf War syndrome. These syndromes can involve many somatic symptoms consistent with possible inflammation. Immunological or neurogenic triggering might account for such inflammation. Serum neopterin, which has an inverse relationship with L-tryptophan availability, may offer a marker of inflammation and macrophage/monocyte activation. We compared middle-aged women with CI (who had high levels of distress) (n=14), depressives without CI (n=10), and normals (n=l1). Groups did not differ in 4 p.m. resting levels of serum neopterin. However, the Clalone had strong positive correlations between neopterin and all of the scales measuring somatization. These preliminary findings suggest the need for additional research on biological correlates of "unexplained" multiple somatic symptoms in subtypes of apparent somatizing disorders.

Altered cytokine production in whole blood cultures of Chronic Fatigue Syndrome patients and a disturbed regulation by glucocorticoids

Authors: J. Visser¹ W. Graffelman² B. Blauw¹, I. Haspels¹, E.R. de Kloet*, and Lex Nagelkerken¹.
¹Division of Immunological and Infectious Diseases, TNO Prevention and Health Leiden
²Division of General Practice, University of Leiden and
*Division of Medical Pharmacolbgy, LACDR, Leiden, The Netherlands.

Recently, we have shown that CD4+ T cells from patients with the chronic fatigue syndrome (CFS) produce less IFN-gamma and display an increased sensitivity to glucocorticoids (GC) with regard to proliferation and IL-4 production (J Infect Dis 1998;177:451-4). Further studies with healthy donors studying IL-10 and IL-12 (two very important regulating cytokines for IFN-gamma) revealed that IL-12 was very sensitive to GC suppression, while IL-10 was relatively resistant (Blood, vol. 91, No. 11 (June 1), 1998: pp 4255-4264). In view of the importance of these cytokines in the regulation of IFN-gamma, we studied the regulation of IL-10 and IL-12 by endogenous and exogenous GC in whole blood cultures of CFS patients. Thirty patients, as well as age- and sex-matched controls, were used in this study. CFS patients showed an increased production of lps induced IL-l0 (p < 0.05), and a reduced production of IL-12 (p=0.06). No differences in sensitivity to dexamethasone (DEX) was detected with regard to TNF-alpha and IL-12 (p40) production, but the patients showed an increased sensitivity with regard to IL-10. Although IL-10 is relatively resistant, we observed that relatively more patients were sensitive for DEX, and approximately 6-fold less DEX was required to suppress the IL-10 production by 50%. This might imply an improper functioning of GC-receptors (GR), since IL-10 production showed an inverse correlation with serum levels of cortisol in the controls, but not in the patients. Further studies regarding the number and affinity of GR in lymphocytes from CFS patients in relation to cytokine secretion are being performed to get more insight in the altered regulation of cytokines by GC in CFS patients.
 

Ixenobiotic toxicity associated with avital (root canal) teeth and associated with Chronic Fatigue Syndrome (CFS)

Authors: Paul R. Chenev MD, Ph.D.; Holly Keever LMT; Elizabeth Furr MT; and Ian Hyams, MD.

Objective:The purpose of this study is to evaluate whether or not root-canal teeth from CFS patients represent a significant source of xenobiotic toxins which have been recently associated with CFS and correlate with severity of illness. Since the pioneering work of Edward C. Rosenow, chief of bacteriology at the Mayo Clinic from 1915 - 1944, it has been known that avital or dead teeth can be a source of infection and human illness. Austin and Cook reported that 89% of avital teeth versus 4% of living teeth were infected by standard culture techniques. Advances in bacteriology, especially anaerobic culture techniques has increased that percentage to over 96% of root filled avital teeth and 98% of non-root filled avital teeth. Recent studies using electron microscopy has shown that 60% of avital tooth infections are bacterial, while 40% are fungal.

Method: Five patients with root canal teeth who met the CDC criteria for CFS were randomly chosen. An in vitro toxicity assay was performed on three extracted teeth at the University of Kentucky using previously published procedures. In brief, this procedure monitors the activity of five enzymes with and without exposure to 100ul of sterile saline in which the root canal tooth has been soaked after two previous soak solutions were discarded. These enzymes are chosen for their ability to bind ATP. The interaction of these enzymes with radioactive analogs of ATP using the technique of photo affinity labeling was measured. Toxic inhibition of the ATP binding site results in fewer radioactive byproducts of the enzymatic reaction which is detected by autoradiography of the protein reaction products. The enzymes are chosen for their sensitivity to a wide variety of toxic compounds which inhibit the interaction of the enzymes with ATP.

Result:All five root-canal teeth extracted from CFS patients exhibited significant toxicity, with an average inhibition of all five enzyme to 35% (range of 21% to 60%) of their control activity without exposure to root-canal toxins. This level of toxicity was observed with a xenobiotic toxin dose estimated at parts-per-billion present at much higher dose in the root-canal tooth. Preliminary outcome studies at one month follow-up suggest that a subset of patients respond significantly to the extraction of this xenobiotic toxicity source. Other studies, presently underway, suggest that the technique of extraction must include attention to the bony elements beneath the tooth to provide optimal outcome.

Conclusion: Recent studies have strongly suggested that xenobiotic toxicity play a substantial role in symptoms related to Chronic Fatigue Syndrome. Efforts to date have centered on the relative toxicity of the portal circulation and the inability of the liver to properly detoxify this substantial source of potential toxicity. Our study suggests that other sources of xenobiotic toxicity, such as root-canal teeth may also be the cause of xenobiotic toxicity linked to CFS. Preliminary studies underway also suggest that the technique of extraction may be critical to optimal outcome and furthermore, extractions of root-canal teeth may not always lead to clinical improvement because it is not the only source of xenobiotic toxicity.

Multiplex PCR for the detection of Mycoplasma fermentans, M. hominis, and M. penetrans in patients with chronic fatigue, fibromyalgia, rheumatoid arthritis and Gulf War Syndrome

Authors: Aristo Vojdani, Al Robert Franco, and Paul Choppa. Immunosciences Lab., Inc. in Beverly Hills, CA and the Arthritis Center of Riverside, CA

Objective: To detect three different mycoplasma species in the blood of patients with overlapping symptomatologies.

Methods: A multiplex polymerase chain reaction (PCR) was developed to detect the presence of mycoplasma genus DNA sequences and to differentiate between three human pathogenic mycoplasma species simultaneously. One set of oligonucleotide primers which is specific for a highly conserved region among all members of the genus mycoplasma, along with three other primer sets which are specific for M fermentans, M. hominis, and M penetrans species were used in this assay. The sensitivity was determined by infecting peripheral blood mononuclear cells (PBMC) of healthy individuals with known bacterial copy numbers from each species, extracting the DNA, and subjecting 1 mg of DNA from each sample to 40 cycles of amplification. By using agarose gel electrophoresis, the detection level was determined to be 7, 7, 9, and 15 mycoplasma cells per mg of human genomic DNA for the M genus, M fermentans, M hominis, and M penetrans primer sets respectively. The assay was applied to DNA samples extracted from the PBMCs of individuals suffering from chronic fatigue syndrome (n=100), fibromyalgia (n=40), rheumatoid arthritis (n=100), Gulf War Syndrome (n=60), and control subject (n=160).

Results: The percent of positive patients with different clinical conditions but with overlapping symptomatologies for different pathogenic mycoplasmas and their comparison with control subjects is presented in the following table.
 
 

 
% Positive For:  Control 
Civilians		 Chronic 
Fatigue
Fibromyalgia		 Rheumatoid 
Arthritis		 Gulf War 
Syndrome		 Control 
Soldiers
M. fermentans 8 32 35 23 36 4
M. hominis 3 9 8 11 5 0
M. penetrans 2 6 4 7 3 0
Significant differences in the presence of these pathogenic mycoplasma species in the blood of patients with different chronic illnesses and control subjects indicate the involvement of this organism in CFS and other related disorders.

Conclusions: These results suggest that multiplex PCR provides a rapid and cost efficient procedure for screening clinical specimens for the presence of three potentially pathogenic species of mycoplasma. Detection of these mycoplasmas by highly sensitive and specific PCR suggests the role of co-pathogens for mycoplasma species in CFS, FMS, RA and GWS, and may contribute to the pathogenesis of fatigue and other symptomatologies associated with these diseases.

Choppa, PC; Vojdani, A; Tagle, C; Andrin, R; and Magtoto, L. Multiplex PCR for the detection of Mycoplasma fermentans, M hominis, and M penetrans in cell cultures and blood samples of patients with chronic fatigue syndrome. Molecular and Cellular Probes, 1998 (in press).

Absence of evidence for Borna Virus infection in Swedish patients with Chronic Fatigue Syndrome

Evengård B, Lee SW, Lind G, Lipkin I Dept of Infectious Disease, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden and Lab for Neurovirology, Univ of California, Irvine

Objective: A majority of patients attending a CFS-polyclinic at a clinic of infectious diseases in Stockholm report an infectious onset. Borna disease virus (BDV) is a novel neurotropic virus reported to be associated with neuropsychiatric disorders. We wanted to investigate the influence of BDV on patients diagnosed with Chronic Fatigue Syndrome.

Methods: A total of 169 patients attending the polyclinic and fulfilling CDC-criteria were investigated. Disease was judged to be severe in 22 patients, and mild in 147. Controls were healthy friends or non-blood relatives to the patients, sex- and age-matched, and random blood donors from a region 100-km northwest of Stockholm. Serum samples were collected and stored as serum and also peripheral blood mononuclear cells were isolated and frozen. ELISA and Western immunoblot were used for antibody detection. Recombinant BDV proteins N, P, and gp 18 were used in both assays. As a negative control antigen beta-galactosidase was used. A nested reverse transcriptase polymerase chain reaction (RT-PCR) was used for analysis of the presence of BDV-P nucleic acid in cells.

Results: There was a high reactivity to control protein beta-galctosidase in ELISA. No specific immunoreactivity to BDV was detected in sera or in cells.

Conclusion: We find no evidence in blood for an involvement of BDV in the pathogenesis of CFS. The high reactivity to the control antigen suggests existence of a polyclonal activation and we are still intrigued by the hypothesis of involvement of a cryptic infection.

Roundworm-like specimens in the sputum of Chronic Fatigue Syndrome patients and controls in open and blind analyses

Author: Lawrence A. Klapow

Objectives:

  • determine the occurrence of a suspected nematode parasite, Cryptostrongylus pulmoni in CFS patients and controls, in both open and blind trials;
  • demonstrate skill in identification through the blind analysis; and
  • preserve specimens for biochemical evaluation.
    • Methods: The distinguishing features of C. pulmoni, primarily male reproductive structures (bursa, genitals, and spicules) and female mouth parts, were first determined from specimens found in the sputum of a patient taking an anti-roundworm medication. Three-day sputum samples were obtained without the use of drugs from 28 CFS patients and 6 controls preserved in 50% ethanol). Patients were drawn from a CFS research center, general medical practices, and an Internet group. Most patients filled out a medical questionnaire. Initial microscopic examination provided candidate specimens, which were preserved in glycerin. An imaging system was used which allowed the mounted specimens to be turned over and photographed from both sides at high magnification (1200X), and various focal depths (a 12X optical video mounted to the l0X ocular of a microscope set at the 10X objective lens). A second polarizer inserted in the ocular lens, as an optical analyzer, sometimes revealed additional structures not visible with the single polarized light source technique.

    Results: Specimens of C. pulmoni, in various states of decay, were found in 11 out of 28 CFS patients, but not in 6 controls, in the combined analyses. The sample size was too small for a chi-squared contingency test. In the blind analysis, 5 of the 11 CFS patients, but none of the 6 controls, were positive. The probability of getting as good a result in a coin toss (random guess) model was 0.01. Of the 11 positives, 10 contained 1 specimen and the other had 2. Re-testing of 3 initially negative patients resulted in 1 positive. Specimens were small: 200 to 500 microns long. Identification required careful evaluation of the photographic images. Three positive patients reported borderline to low-grade eosinophilia (6-9%). Stool tests were negative.

    Conclusion: Decayed specimens of a suspected roundworm, Cryptostrongylus pulmoni (provisional) "the hidden lung worm", were found in the naturally expelled sputum of 39% of CFS patients, but not in 6 controls. Low test sensitivity suggests that actual occurrence is likely to be higher. A larger test design will be needed to evaluate the possible association of C. pulmoni with CFS. A random guess model suggested that skill in identifying C. pulmoni, rather than chance, governed the results of the blind analysis. Current diagnostic methods would not be expected to detect C. pulmoni. The usual indicators of nematode infections, high-grade eosinophilia and positive stool tests, were not apparent. In addition to being decayed, specimens were also very small and rare, and required specialized imaging techniques for identification. Roundworm infections can produce immune abnormalities like those reported in CFS, including low serum cortisol, altered anti-viral responses, eosinophil anomalies, and altered cholinergic processes.

    Borna Disease Virus proteins in patients with CFS

    Authors: Susan Levine, MD; Ian Lipkin, MD; and Shaun Lee

    Objective: Bornavirus is a member of a newly recognized virus family, Bornaviridae, and is neurotropic for a wide range of animal species, including birds, rodents, horses and humans. Although little is known about its mode of transmission and it has not been clearly linked to any human disease, an association between bornavirus and neuropsychiatric diseases has been suggested. We sought to study the prevalence of Borna Disease Virus (BDV) proteins in a non-select group of CFS patients.

    Methods: 110 serum samples from 77 CFS patients and 33 healthy controls were examined for evidence of BDV infection using an ELISA based on 3 recombinant BDV proteins, nucleoprotein (N), phosphoprotein (P), and matrix protein (M). An irrelevant protein, beta-galactosidase (Beta-gal), was used as a control for the specificity of immunoreactivity to BDV proteins. Initial screening for reactivity was performed at a dilution of 1:25.

    Results: 15 samples were immunoreactive to one or more recombinant BDV proteins (#3, #6, #8, #11, #17, #18, #23, #24, #27, #33, #36, #41, #59, #93, #108) and were re-assayed in a secondary screen using the same parameters. Of these, samples #3 and #33 were normal controls. The six samples which were immunoreactive in the secondary screen to 2 or more BDV proteins were selected for a tertiary screen using serum dilutions of 1:25 and 1:50. All samples selected for rescreening had consistent reactivity in consecutive assays, and Optical Density measurements were consistent in all 3 screenings. Dilution of serum from 1:25 to 1:50 in the tertiary assays resulted in a measurable decrease in O.D. measurements in the immunoreactive samples. All samples were immunoreactive to beta-galactosidase, and may reflect differences in methods used in serum collection. Sample #93 appeared to be the most immunoreactive, and we believe it would be worthwhile to further study serum from this patient using Western Blot and Immuoprecipitation, as well as mononuclear cells using molecular methods of detection of viral nucleic acids such as PCR methods.

    Conclusion: Although no serum sample demonstrated specific immunoreactivity to BDV proteins (all were immunoreactive to beta-gal) several samples were immunoreactive to 2 or more BDV proteins. Immunoreactivity to 2 or more BDV proteins is consistent with BDV infection in other systems. If clinical correlation supports a potential role for viral infection we recommend pursuing further studies.

    Infective agents in patients with CFS

    Authors: McGill M, Simpson K, Behan WMH, Gow JW and Behan PO.
    Glasgow University Dept of Neurology, Southern General Hospital, Govan Rd, Glasgow G51 4TF, Scotland.

    Objective: Chronic fatigue syndrome (CFS) is often thought to follow a viral-like episode. Although many infectious agents have been associated with CFS, no single agent has been isolated or identified. As part of our long-term programme to elucidate the pathogenesis of CFS, in this study six specific infectious agents were sought in tissue from patients with CFS. These include the DNA viruses varicella zoster virus and hepatitis B; the RNA viruses Borna disease virus, enteroviruses and Influenza B; and Brucella, as chronic Brucellosis may present with a condition similar to CFS. The study was carried out in order to confirm or eliminate these organisms as possible chronic pathological agents, to identify patients with recurrent or chronic infection which could indicate any immune system abnormality and to identify subgroups of patients.

    Methods: A two-year double-blind study was undertaken with 64 patients with CFS, and 34 carefully age/sex/geographical location/time-of-sampling matched controls. Following a full clinical screening, peripheral blood samples were taken for peripheral blood mononuclear cell (PBMC) isolation and, in certain cases, lumbar puncture for cerebral spinal fluid or liver biopsy was performed. PBMC nucleic acids were prepared from patients and controls prior to PCR amplification for Brucella and the DNA viruses, and RT-PCR amplification for the RNA viruses, followed by Southern blot analyses and hybridisation with internal oligonucleotide probes.

    Results: The data presented here represents PCR analyses on nucleic acids extracted from PBMC samples.

     
     
      CFS Patient Control
    VCV: 3 +ve 0 +ve
    hepatitis B: 4 +ve 0 +ve
    BDV: 3 +ve 0 +ve
    enteroviruses: 0 +ve 0 +ve
    influenza B: 0 +ve 0 +ve
    Brucella: 2 +ve 0 +ve
    Conclusion: Of the 64 patients studied, 3% had a current Brucella infection, 6% were infected with hepatitis B, 4.6% with VZV and 4.6% with BDV. Overall, 18% of the patients had evidence of infection, although that figure would be reduced to 14% if the VZV positive cases were due to a sub-clinical reactivation of latent virus rather than a recent infection. None of the infectious agents were present in a significantly high number of cases of CFS and none of the patients had evidence of dual infection. The data highlights one difficulty of working with patients with CFS -- patients who have been diagnosed as having the disorder may be suffering from undiagnosed less common infections. Data from subsequent research into CFS may be inaccurate due to a dilution of the true patient cohort.

    The relationship between Chronic Fatigue Syndrome, fibromyalgia and chemical sensitivity

    Authors:Aristo Vojdani and Paul Choppa. Immunosciences Lab., Inc. Beverly Hills, CA.

    Objective: Overlapping symptomatologies between Chronic Fatigue Syndrome and Chemical Sensitivity have been observed by different investigators. Therefore, it is of great importance to develop biomarker(s) for possible differentiation between viral induced CFS (without sensitivity to chemicals) versus chemically induced CFS. Since interferon induced proteins 2-5A Synthetase and protein kinase RNA (PKR) have been implicated in viral induction of CFS, the objective of this study was to utilize 2-5A and PKR activity for the differentiation between CFS induced by either viruses or chemicals.

    Methods: Based on the CDC definition and criteria, twenty CFS patients who were positive for viral genome(s) [mainly HHV6; HTLVl, EBV, and CMV] and did not have any history of exposure to chemicals were included in this study. For comparison, the second group of patients consisted of twenty individuals from the same geographical area who were negative for viral genomes but had been exposed to methyl tertiary-butyl ether concentration of up to 70 ppm and benzene concentration up to 14 ppm. All patients complained of fatigue and other symptoms which were overlapping with the viral genome positive CFS group. From all 40 patients, blood was drawn, leukocyte extract was prepared and assayed for 2-SA Synthetase and PKR activity.

    Results: Clinical specimens which were positive for viral genomes showed from 2.2-38.7 and 1.3-13.5 fold increase in 2-5A and PKR activities over the background of the healthy controls respectively. Similarly the second group (negative for viral genomes, but exposed to chemicals) showed 1.1-29.2 fold increase for 2-5A Synthetase and 1.3-11.6 fold increase for PKR when they were compared to healthy subjects. To elucidate mechanisms involved in viral versus chemical induction of 2-5A Synthetase and PKR, MDBK cell lines were cultured in the presence or absence of HHV6, MTBE, or Benzene. In addition, MDBK cells were incubated with heat shock proteins and interferon-beta. 2-5A and PKR activities were measured in all the above conditions. A clear induction of 2-5A and PKR was observed when MDBK cells were exposed to HHV6, MTBE, and Benzene. This induction was more significant with HSP90, HSP70, and INF-alpha, indicating their involvement in the mechanism of action.

    However, when MDBK cells were incubated either with MTBE + Benzene or HHV6 in the presence or absence of anti INF-beta or anti HSP-70, the activities of both 2-5A and PKR in HHV6 infected MDBK cells were inhibited by more than 90% by anti INF-beta, and only 20% by addition of anti HSP70. While in MTBE + Benzene exposed cells anti INF-beta reduced the activity of these enzymes by 40% and anti HSP7O by more than 90%. This indicates an involvement of INF-beta in viral induction 2-5A and PKR and HSP involvement in chemical induction of these enzymes.

    Conclusion: We conclude that 2-5A and PKR are not only biomarkers for viral induction of CFS, but biomarkers for other stressors inducing CFS which include MTBE and Benzene. Interferon-beta is involved in the induction of 2-5A and PKR in CFS patients, and HSP is more involved in this mechanism of action induced by toxic chemicals.
     

    Postural Orthostatic Tachycardia And Chronic Fatigue: a distinct subset of Neurally-Mediated Syncope in adolescents

    Authors: Mark E. Alexander M.D., Charles Berde, M.D, Ph.D., John K. Triedman, M.D., Robert Sundel, M.D., J. Philip Saul, M.D.
    Departments of Cardiology, Anesthesia and Medicine, Children's Hospital, Boston, MA

    Background: Some patients with chronic fatigue syndrome (CFS) have findings of neurally-mediated syncope. We report initial results of evaluation and therapy in 26 adolescents (18 females, mean 15.7 ± 2.4 yrs) with > 6 months of debilitating symptoms including fatigue, orthostatic intolerance and multiple somatic symptoms. Head up tilt (HUD) was performed at 600 for 12 minutes. Ten patients underwent concomitant Doppler monitoring of middle cerebral artery blood flow velocity (CBFV). Hemodynamic responses were compared with 20 patients with isolated syncope (SYNC), 12 who had CBFV monitoring.

    Results: Initial supine HR, systolic and diastolic BP, and CBFV were similar for the two groups. Compared to SYNC patients, CFS patients had greater increases of HR, higher maximum HR, larger decreases in CBFV, but unchanged BP during the first 3 minutes of HUT (figure). Overall, 6/26 (23%) of CFS patients had syncope, compared with 5/20 (25%, p = ns), while 15/26 (58%) of CFS patients had postural orthostatic tachycardia (POTS) with greater than 40 bpm increase in HR, compared with 4/20 (20%) of the SYNC group. While the supine response to isoproterenol was comparable, CFS patients had higher heart rates with early tilt (153 ± 18.6) compared with syncope patients (125 ± 33.1). Therapy for orthostatic intolerance in the CFS group improved reported well-being, on a 0-10 scale, from 3.9 ± 1.6 to 8 ± 1.7 (p < .001).

    Conclusions: CFS patients have a distinct response to orthostatic stress, with excessive tachycardia and decreased CBFV early in HUT as well as an exaggerated response to isoproterenol infusion. Therapy directed at orthostatic incompetence appears to improve overall well-being. More precise physiologic studies are required to understand this group of patients.
     

    Working capacity measured by bicycle testing in CFS and fibromyalgia patients

    Authors: P. De Becker, E. Joos, I. Campine, E. Van Steenberge, J. Roeykens, A. Leys, K. De Meirleir.

    Objective: Chronic Fatigue Syndrome and fibromyalgia are clinically resembling disorders in which muscle pain, muscle weakness and intolerance to physical exertion are characteristic. The CDC-criteria for CFS require a reduction of at least 50 % in the ability to perform activities of daily living. The purpose of this study was to evaluate whether this disability could be objectivated.

    Methods: 305 CFS-patients (252 female and 53 male) who fulfilled the 1988 CDC-criteria for CFS, 226 fibromyalgia patients (140 female and 86 male) and 308 healthy controls (208 female and 100 male) performed a maximal exercise test on a electrically braked bicycle ergometer, and continuous gas exchange measurements were made. The groups were matched for sex and age. The following parameters were measured: heart rate in rest, maximal heart rate (HR max), maximal work capacity (MCW) attained, MCW per kg of body weight (Watt max/kg), maximum oxygen uptake per kg body weight (VO2 max/kg), HR at RQ 1, Watt at RQ = 1, percentage of target heart rate.

    Statistical analysis was performed using the Mann-Whitney test.

    Results:
    The main results were:
    FEMALE CFS Fibromyalgia  Control
    HR max (bpm) 147* ± 23 152* ± 24 167 ± 17
    W max/kg (Watt/kg) 1.42 ± 0.42 1.36 ± 0.45 2.90 ± 0.75
    VO2max/kg (ml/min/kg-1)  20.7 ± 8.2 19.4 ± 5.6 32.42 ± 7.36
    MALE CFS Fibromyalgia  Control
    HR max (bpm) 157* ± 23 149* ± 169 ± 13
    W max/kg (Watt/kg) 2.12* ± 0.72 1.69* ± 0.59 3.62 ± 0.48
    VO2max/kg (ml/min/kg-1)  28.4* ± 11.6 22.9* ± 6.6 39.22 ± 4.84

    * = p > 0.01 compared to Control population

    Conclusion: CFS and fibromyalgia patients have a working capacity that is at least 40% lower compared to controls, which objectively proves their physical disability.

    The majority of patients achieved the anaerobic threshold, but not 85% of THR (data not shown). We postulate that this is due to a severe muscle weakness, and not to deconditioning.

    Respiratory symptoms and lung function testing in Chronic Fatigue Syndrome (CFS) patients

    Authors: P. De Becker, I. Campine, E. Van Steenberge, M. Noppen, A. Leysl, K. De Meirleir

    Objective: The purpose of this study is to report the prevalence of respiratory symptoms in a cohort of CFS patients and to assess the usefulness and importance of pulmonary function testing in the clinical management of these patients.

    Methods: A sample of 55 consecutive CFS patients, who met the CDC (1988) and Fukuda (1994) criteria, were recruited from a university-based fatigue clinic in Brussels, Belgium. The following respiratory symptoms were observed in 46 of these patients (9 CFS patients did not present any respiratory symptoms at all): cough (19/55), medical history of allergy (8/55), new onset of allergy (16/55), chest tightness (6/55) and the major respiratory complaint appeared to be a pronounced exercise induced dyspnea (39/55).

    A control group consisted of a community based sample of 39 age-and sex-matched individuals, not seeking medical care, and specifically denying any CFS related symptoms. Furthermore, they did not present any respiratory symptoms. Only 10 subjects showed a medical history of allergy (2 penicillin, 8 hayfever/house dust).

    All patients and controls underwent a standardized pulmonary function testing, measuring following parameters: forced vital capacity (FVC), forced expiratory volume in one second (FEV1), functional residual capacity (FRC), residual volume (RV), vital capacity (VC) and total lung capacity (TLC).

    In all CFS patients, a histamine broncho-provocation test was additionally performed to determine the presence of bronchial hyper-responsiveness (defined as PD20 his < 2 mg histamine).

    Statistical analysis was performed using descriptive statistics and a nonparametric Mann-Whitney test.

    Results: Compared to controls (A), CFS patients (B) do not show a significant difference in TLC (mean ± SD, A: 5.94 L ± 1.04 L; B: 5.72 L ± 1.005; p = 0.37). However, we found a significant difference between both groups in VC (A: 4.74 L ± 0.90 L; B: 4.255 ± 0.849; p < 0.01) and in RV (A: 1.19 L ± 0.33 L; B :1.479 ± 0.494; p < 0.01). In 33/55 (60%) patients a marked bronchial hyper-responsiveness was present.

    Conclusion: CFS patients show a significant decrease in VC, possibly due to a significant increase of RV. The incidence of bronchial hyper-responsiveness in this group is also remarkably high. These observations can, at least partially, explain the respiratory symptoms in these patients.
     

    No evidence for elevated Substance P levels in cerebrospinal fluid of patients with CFS

    Evengård B, Nilsson CG, Lindh G, Lindquist L, Eneroth P, Fredrikson S, Terenius L, Henriksson KG.
    Dept Infectious Disease, Unit for applied biochemistry clinical research center, Dept Neurology, Karolinska Insitutet at Huddinge University Hospital, Dept of Drug Dependence Research, Karolinska Hospital, Stockholm, and Neuromuscular Unit and Pain Clinic, University Hospital, Lirköping, Sweden

    Background: Substance P (SP) is a neuropeptide involved in the neurotransmission of pain from periphery to the central nervous system. It has been reported that SP in the cerebrospinal fluid is markedly elevated in patients with Fibromyalgia. As Fibromyalgia and CFS are conditions which share some symptoms, we wanted to investigate the levels of SP in the cerebrospinal fluid of CFS patients.

    Methods: Cerebrospinal fluid was obtained from 15 patients (9 women, average age 39.3 years) fulfilling CDC-criteria for CFS but not for Fibromyalgia. The sample was immediately centrifuged at +4°C for 10 min. at 1000g to remove cells. Rapid cooling was performed. The sample was stored in plastic cryogenic tubes and stored frozen at -70°C. An radioimmunoassay was used to analyze the sample. For comparison, cerebrospinal fluid drawn from 13 patients with cerebrovascular disease (7 women, average age 65 years) was treated and analyzed in the same manner. All samples were analyzed blindly.

    Results: All values of SP of the CFS patients were within previously reported normal range of SP in cerebrospinal fluid. In the control group, 2 patients had slightly increased values.

    Conclusion: The results support the notion that FM and CFS are different disorders in spite of overlapping symptomatology.

    Upregulation of Ca2+ ion channels in patients with CFS

    Gow JW, McGill M, Behan WMH, Simpson K & Behan PO
    Glasgow University Dept of Neurology, Southern General Hospital, Govan Rd, Glasgow 051 4TF, Scotland.

    Objective: Chronic fatigue syndrome (CFS) is a clinical condition of unknown ætiologies and the specific abnormalities which explain the persistent fatigue and myalgia are unclear. Viruses, often implicated as initiators of CFS, affect cell membrane ion channels. For instance, HIV gp120 proteins can alter calcium flux through voltage-dependent calcium ion channels and picornavirus VP1 can mimic insect charybdotoxin and induce changes in Na/K monovalent cation channels. CFS also shows some similarity with ciguatera food poisoning, which is caused by toxins known to act on cell membrane ion channels. Excessive calcium influx leads to the depletion of energy reserves by activating Ca2+-ATPase and impairs mitochondrial oxidative phosphorylation. The aim of this study was to examine the expression of genes related to Ca2+ ion handling in the muscle of patients with CFS.

    Methods: Skeletal muscle biopsy RNA was prepared by the AGPC method from 16 patients with CFS and 16 age and sex-matched healthy controls. We examined the levels of RNA encoding the sarcoplasmic reticulum Ca2+-ATPase (SERCA 1) and the a1 subunit of the dihydropyridine-sensitive (DHP) Ca2+ channel receptor. Two methods were employed in order to quantitate the RNA from the biopsies, including Southern blot analysis with oligonucleotide probe hybridisation and RT-PCR. The human actin gene was used as a baseline reference for each sample, and results were measured by densitometry.

    Results: From independent multiple experiments, densitometric readings were analysed on the Herolab E.A.S.Y.Plus enhanced documentation system. The levels of the Ca2+-ATPase RNA and the DHP receptor RNA were increased compared with the control samples.

    Conclusion: This data is indicative of an upregulation of expression of the skeletal muscle genes involved in Ca2+ handling in patients with CFS. We had previously also looked at the ryanodine receptor of the Ca2+ release channel of the sarcoplasmic reticulum and Na+/K+ ATPase, but had noted no difference in signal. The data presented here may suggest that abnormal Ca2+ flux is present in the skeletal muscle of patients with CFS and warrants further investigation.

    Association of intracranial abnormalities between rCBF and acetyl-carnitine uptake in patients with CFS studied by PET

    Hirohiko Kuratsune¹:*, Kouzi Yamaguti¹*, Gudrun Lindh², Birgitta Evengård², Takashi Machii¹, Kiyoshi Matsumura*, Bengt Långström³, Yuzuru Kanakura¹, Teruo Kitani° and Yasuyoshi Watanabe*
    ¹Hematology and Oncology, Osaka Univ. Med. School., Osaka 565, Japan
    ²Department of Infectious Disease, Karolinska Inst., Huddinge Hospital, Stockholm, S-141 86, Sweden
    *Osaka Bioscience Inst., Osaka 565, Japan
    ³Uppsala Univ. PET Centre, UAS, S751 85, Uppsala, Sweden
    °Sakai Municipal Hospital, Osaka 590, Japan.

    Recently, we found a serum acylcarnitine (ACR) deficiency in the vast majority of patients with chronic fatigue syndrome (CFS). There is a clear correlation between serum ACR concentrations and the levels of fatigue. More recently, we succeeded in synthesizing acetyl-L-carnitine labeled with 11C, and thus making it possible to study the dynamics of serum acylcarnitine. From our recent studies, it became clear that mammals have a certain regulatory system of serum acylcarnitine in the liver, and that serum acylcarnitine has a very important physiological role for the brain, that is, conveying an acetyl moiety into the brain.

    Objective: To clarify whether or not the abnormality of acetyl-carnitine metabolism in the brain might be associated with the pathogenesis of CFS, we studied not only the uptake of acetyl-L-carnitine labeled with 11C into the brain (ACR uptake) but also regional cerebral blood flow (rCBF) in 8 patients with CFS and 8 age- and sex-matched controls in Sweden.

    Methods: The rCBF was studied using a bolus of intravenous radioactively labeled water (H215O), and ACR uptake into the brain was studied using [2-11C] acetyl-L-carnitine. All of individual data were put into one model of standardized brain atlas, and we compared the rCBF and ACR uptake between the CFS group and the control group.

    Results: The CFS group had a lot of brain regions where rCBF decreases. That is, very low levels of rCBF were found in a part of Brodmann 24(r), 33(r), 37(l), and low levels of rCBF were found in a part of Brodmann 9(l), 10(l), 11(l), 12(r,l), 13(r), 18(r,l), 19(r,l), 21(r,l), 22(r,l), 24(l), 32(r), 33(l), 36 (r,l), 37 (r), 38(r,l), 39(l), 43(l), 44(l), 47(r), insula (r,l), thalamus (r,l), putamen(r,l), hippocampus (r,l), parahippocampal regions (l), amygdala (l), N. caudatus (l), mesencephalus, pons and cerebellum. On the other hand, the reasons which showed lower ACR uptake in CFS group were restricted, and the main reason was Brodmann 24 (r,l). ACR uptake abnormalities were also found in Brodmann 9(l), 21(l), 22(r,l), 33(r,l), 36 (l), insula (l) and cerebellum, but they were frequently dissociated with rCBF abnormalities. There was no reason in CFS group which had higher levels of rCBF and ACR uptake compared to control group.

    Conclusion: Intracranial abnormalities of ACR metabolism might be related to the pathogenesis of CFS, in addition to the rCBF abnormalities.

    Heterogeneity of symptom, onset and biochemical profiles in "defined" CFS patients

    Authors: McGregor NR¹*, Hoskin L², Dunstan RH¹, Clifton Bligh P², Butt HL¹, Fulcher G², Roberts TK¹. Dunsmore J², Zerbes M¹, Klineberg IJ*
    ¹Collaborative Pain Research Unit, Department of Biological Sciences, The University of Newcastle, Callaghan, NSW 2308,Australia.
    *Neurobiology Research Unit, Centre for Oral Health, Research University of Sydney, Westmead Hospital, Westmead, NSW 2084 Australia
    ²Department of Endocrinology, Royal North Shore Hospital, St Leonards, NSW, Australia.

    Objective: To assess the symptom, biochemical and onset data of patients who comply with the CFS definitions to assess whether they are either homogeneous or heterogeneous. The CFS definition requires the exclusion of other known fatigue-related diseases and compliance with a primarily host-response associated symptom constellation.1,2 The patient set derived by this process is heterogeneous in their psychological presentation, and no single ætiological agent or event has been found using this definition.

    Methods: Multiple regression analysis and clustering techniques were applied to several CFS study data sets to detect either homogeneity or heterogeneity of the patients symptoms, onset events, urinary amino and organic acid, and serum lipid profiles.

    Results: CFS patients divided on the basis of host responses, infectious responses, sudden or gradual onset or type of onset, had different symptom and biochemical constellations. The disturbances of urinary amino and organic acid excretion could distinguish CFS patients from controls, but the events associated with fatigue or muscle pain, common to all CFS patients, were not selective for defined CFS. Common fatigue-associated host response changes could not be specifically associated with any onset event or psychological response. However alterations in the excretion of various metabolites could be associated with different onset, symptom and psychological response patterns. In a similar manner, the plasma fatty acids profile could differentiate defined CFS patients from control subjects but the differentiating patterns did not occur in all defined CFS patients. The lipid profiles associated with current viral infections, such as EBV, or post-EBV infection were not distinguishing factors for defined CFS. The major lipid changes distinguishing CFS patients from controls appear to be of genetic or acquired origin. Multiple regression and clustering techniques revealed 5 basic types of CFS lipid profiles, whilst the control group had a high degree of homogeneity. These CFS lipid changes are associated with known lipid disorders and provided evidence of heterogeneity.

    Conclusion: The current CFS definitions either lack standardization and/or the CFS exclusion criteria are insufficient to determine all additional excludable fatigue disorders. The capacity to group currently defined CFS patients into subsets using objectively derived measurements, many of which may indicate known disease states, represents a major advance in CFS research.

    References:
    ¹Holmes OP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: A working case definition. Ann Intern Med 1988; 108:387-389.
    ²Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: A comprehensive approach to its definition and study. Ann Intern Med 1994; 121:953-959.

    Exercise overtraining as a possible risk factor for Chronic Fatigue Syndrome

    Authors: J.P. Montalván M.S. C.S.C.S., Fitness/Works LLC
    Paul H. Levine, M.D., George Washington University School of Public Health and Health Services

    Objective: To report case histories of Chronic Fatigue Syndrome (CF S) occurring in two female athletes who were overtraining, and to describe a possible mechanism.

    Methods: Severe and acute-onset CFS was diagnosed in two female athletes involved in vigorous exercise programs at the onset of their symptoms. The athletes were suspected to have overtrained prior to their diagnosis of CFS. The athletes were interviewed regarding the onset of CFS, exercise history by type and duration, and concurrent symptoms related to CFS and overtraining. A literature search was performed and physiological and psychological mechanisms involved in overtraining were compared with immune abnormalities reported in CFS.

    Both female athletes reported symptoms consistent with those associated with overtraining, including decreased athletic performance, increased stress, and depression prior to their diagnosis of CFS (Phys. Sports Med. 19(5):l 12-118, 1991). Both reported similar occurrences in athletes of their acquaintance who were also overtraining. While some research demonstrates moderate exercise improves immune function, some literature suggests a decline in immune function and responsiveness in overtrained endurance athletes. Furthermore, some clinicians and coaches believe muscular fatigue lowers resistance and is a predisposing factor to infectious disease (J Strength and Cond. Res. 8(4): 251-254, 1994).

    Infection has been implicated as a possible cause of CFS, and possible risk factors for the development of CFS include history of depression, stress and exercise (Am. J Med. 100: 548-54, 1996). Given the immunoregulatory abnormalities believed present in CFS patients, overtraining may have contributed to the athletes' increased risk of infection. Furthermore, the athletes' overtraining symptoms may have increased their susceptibility to the development of CFS.

    Conclusion: The occurrence of CFS in the two case histories evaluated and the report by MacDonald et al. of stress, depression and exercise as risk factors for CFS support the possibility that overtraining may be a risk factor for CFS. A more systematic study of athletes regarding this hypothesis is proposed.
     

    Measurement of postural stability in patients with Chronic Fatigue Syndrome

    Authors: Paul L ¹ and Wood L.²,
    ¹Division of Physiotherapy and ²Department of Biological Science, Glasgow Caledonian University, Glasgow, Scotland.

    Objective: Virtually all neuromusculoskeletal disorders may result in impaired balance. It is broadly estimated that between 30% and 70% of subjects with Chronic Fatigue Syndrome (CFS) suffer from dysequilibrium. Maintenance of balance requires visual, somatosensory and vestibular input, central processing of this information, and a co-ordinated motor response. Balance is not a static process. Continuous postural adjustments are necessary to keep the body upright even during quiet standing. These postural adjustments can be quantified by using a force plate to examine the movement of the body's centre of pressure. The aims of this study were:

    Methods:Ten CFS subjects and ten sedentary age and sex-matched controls took part in the study. Postural stability was assessed using a Kistler force plate. Subjects stood on the Kistler force plate and the position of their Centre of Pressure (COP) was recorded at 250Hz. The movement of the COP in both the anteroposterior and mediolateral directions was recorded, as was the total excursion of the path of the COP. Each test lasted 25 seconds and was performed under eyes-opened and eyes-closed conditions. Balance assessment was performed before subjects completed a 15 minute steady-state exercise test. The exercise was carried out on a cycle ergometer, where subjects cycled at 90% of their predicted work rate at their anaerobic threshold based on age, sex and weight. Balance assessment was repeated immediately after the exercise, then at 20 minute intervals for the subsequent hour, and reassessed 24 hours later.

    Results: Preliminary data analysis suggests that, in general, before exercise, postural stability was not significantly different between CFS subjects and controls. Unsurprisingly, for both groups, postural sway was greater under eyes-closed conditions. In both groups, CFS and control, it would appear that exercise did not alter postural stability when subjects stood with their eyes-opened. Under eyes-closed conditions, however, subjects with CFS had poorer balance following the exercise period. Balance was not adversely affected by exercise in the control group under eyes closed conditions.

    Conclusions: Static balance, as assessed by the Kistler force plate, is not affected by CFS. It is known that static balance tests may not be sensitive enough to investigate minor dysequilibrium problems associated with some pathologies, therefore further study, in progress, aims to investigate more dynamic balance in CFS subjects. Exercise did not affect the balance of either CFS subjects or controls in eyes-opened conditions, however with eyes closed, CFS subjects exhibited greater postural instability. Further study is required, however, this finding may lend support to the anecdotal evidence that activity can exacerbate the symptoms of CFS.

    The electroencephalogram as a diagnostic marker for Chronic Fatigue Syndrome (CFS)

    Authors:Myra Preston Ph.D. and Charles W. Lapp, M.D., Charlotte, North Carolina

    Research efforts have failed to uncover a diagnostic marker for CFS. This study looks to the brain as the site of a possible diagnostic marker that would be sensitive and specific to the illness of CFS. The objective of this study is to differentiate CFS subjects from controls in a blinded fashion. To differentiate the two populations, we utilize an EEG pattern that was present in approximately 280 persons with CFS (PWCs), that we had previously studied in an unblinded fashion in the 24 months prior to this study. This brain abnormality was not present in other patient populations or controls.

    Methods: We used a blinded protocol to collect raw EEG data in patients that met the CDC case definition of CFS. Controls were screened for current and/or potential exposure to health problems to insure that participants did not have prolonged fatigue or an acute illness.

    Results: PWCs were correctly identified with 80% sensitivity and 82% specificity compared to healthy controls. Four files utilized as an internal positive control were selected with 100% consistency.

    Conclusions: EEG data can be used to differentiate PWCs from controls with high sensitivity and specificity. The specific EEG signature seen in persons with CFS can be a diagnostic disorder for the disorder.

    Brain SPET in Chronic Fatigue Syndrome

    Authors: D. Di Giuda,¹ G. De Rossi,¹ D. Racciatti,² A. Barberio,² E. Pizzigallo²
    ¹Nuclear Medicine Department, "A. Gemelli" Catholic University of Rome, Italy
    ² Clinic of Infectious Diseases, "G. D'Annunzio" University of Chieti

    Objective: Chronic Fatigue Syndrome (CFS) is a severely disabling illness of uncertain ætiology, characterized by somatic and neuropsychiatric symptoms. At present, there is no clearly defined diagnostic test for the syndrome. This study was designed to investigate possible changes in the brain perfusion of patients with CFS.

    Methods: Forty patients with suspected CFS underwent 99mTc-HMPAO SPET; 31 of them fulfilled the CFS diagnostic criteria of the Centers for Disease Control (CDC) of Atlanta. A 30 min examination with a brain-dedicated multicamera system was performed 10 mm after 925 Mbq 99mTc-HMPAO i.v. injection. A SPET analysis with a predefinite 26 ROI template yielded some semi-quantitative parameters.

    Results: Regional brain perfusion impairment (mainly hypoperfusion) was found in 26 (83.9%) of 31 CFS patients, in comparison with 20 age-matched control subjects. In 8 (30.8%) of these 26 patients, a concurrent fibromyalgia syndrome was present. All patients had normal findings on MR images. On the basis of psychiatric tests, mood disorders (38.7%), personality abnormalities (29.3%) and other psychiatric disorders (22.0%) occurred in CFS patients. A total of 147 brain regions showed abnormal 99mTc-HMPAO uptake: 132 cortical and 15 subcortical areas. The most frequent abnormalities were found in the following middle-anterior cortical regions (with a low left hemisphere prevalence): anterior frontal (16), sylvian (16) and middle frontal (14) areas. In relation to associated psychiatric symptoms, the highest number of impaired regions was present in the personality abnormalities and in the group of other psychiatric disorders (71.2% and 61.4% of middle-anterior cortical areas hypoperfusion, respectively).

    Conclusion: This study confirmed previous reports of brain perfusion impairment in CFS, providing objective evidence of CNS dysfunction. On the basis of our results, 99mTcHMPAO SPET seems to carefully assess cerebral perfusion abnormalities in CFS, simultaneously allowing a comparison with related psychiatric disorders. This may be useful in CFS prognosis and therapy planning.

    Neurally-Mediated Hypotension and Chronic Fatigue Syndrome: preliminary results

    Authors: A. Sisto,¹ P. Lanzillotta,² A. Ceccomancini,¹ P. Di Paima,² D. Racciatti,¹ G. Abate² and E. Pizzigallo¹
    ¹Clinic of Infectious Diseases and
    ²Department of Gerontology, "G. D'Annunzio" University of Chieti, Italy

    Chronic Fatigue Syndrome (CFS) is a clinical syndrome consisting primarily of fatigue and cognitive dysfunction. The etiology and pathogenesis of CFS remain unclear. Many authors report a correlation between CFS and dysfunction of the autonomic neurological system.

    Objective: In this study, we evaluated the possible correlations between Chronic Fatigue Syndrome and neurally-mediated hypotension.

    Methods: 10 patients satisfying the Centers for Disease Control criteria for the diagnosis of CFS were preliminarily enrolled. All subjects were evaluated with upright tilt-table test in a quiet room. Blood pressure was detected by "FINAPRES" (Ohmeda-Lousville, Colorado) and an electrocardiogram was continually performed by a monitor. After 10 mm supine, the patients were tilted upright to 600 for 45 min. If a positive response was not observed after 30 min., a sublingual tablet of nitroglycerin was administered. A positive response was defined as a decrease in blood pressure more than 60% of basal value, presyncope, or syncope.

    All patients were evaluated for Valsava test and hand-grip test, also.

    Results: All patients showed negative response after 30 min. on the tilt-table; 3 patients (30%) showed a positive response after sublingual administration of nitroglycerin. The Valsalva test and the hand-grip test in all subjects were negative.

    Conclusions: Tilt-table test is an important system for the evaluation of neurally-mediated hypotension in patients with structurally normal heart. The association between CFS and neurally-mediated hypotension is reported. Our data suggest this correlation, but others' investigations seem to detect more of a pathogenetic mechanism of fatigue in subjects with neurally-mediated hypotension. Finally, neurally-mediated hypotension may be a possible cause of fatigue in patients with CFS.