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Index to Abstracts from AACFS Conference October 1998


Abstracts of Papers Presented at
The Bi-Annual Research Conference of the
American Association for
Chronic Fatigue Syndrome (AACFS)

October 10-11, 1998 -- Cambridge, Massachusetts

Poster Session 2: Clinical

Co-chairs: Dedra Buchwald, M.D., and David Klonof, M.D.
October 10, 1998, 3:30 pm-4:00 pm

1. 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?
D. Berg, L.H. Berg, J. Couvaras
2. Growth hormone secretagogue therapy provides effective relief of most symptoms related to Chronic Fatigue Syndrome in a prospective patient centered outcome study
Paul R. Chencv,MD., Ph.D., Holly Keever, LMT
3. An overview of Ampligen and experience in a small cohort
Charles W. Lapp, M.D., Cynthia S. Voyles, A.N.P., M.S.N., Patricia Davis, C.M.A. and Sheila Langford, R.N.
4. 5 year follow-up of young people with Chronic Fatigue Syndrome following the double-blind randomised controlled intravenous gammaglobulin trial
Rowe, K.S.
5. Effective treatment for Fibromyalgia and Chronic Fatigue Syndrome: a placebo controlled study
J.E. Teitelbaum, M.D.; B. Bird, M.T., C.L.S.; R. Greenfield, M.D; A. Weiss, M.D.; L. Muenz, Ph.D.; L. Gould
6. The use of serine in the management of Chronic Fatigue Syndrome
Rosamund Va1lings, M.B., B.S.


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?

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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.

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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.

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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.

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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.

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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

Thanks to Carolyn Viviani for scanning in this abstract.

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