1999 Sydney ME/CFS Conference|
Abstracts & Posters Abstracts & Posters Presented at Conference
Prof Garth L. Nicolson, Marwan Nasralla, PhD, Goerg Haier, MD and Nancy L. Nicholson, PhD.
The Institute for Molecular Medicine, 15162 Triton Lane, Huntington
Beach, CA 92649, USA
Patients with chronic illnesses, such as chronic fatigue syndrome (M.E.), fibromyalgia syndrome (FMS), Gulf War illness (GWI) or rheumatoid arthritis (RA), often have overlapping signs and symptoms. We have found that a major source of their morbidity is caused by various chronic viral and bacterial infections. For example, GWI patients slowly present with chronic, complex, multiorgan signs and symptoms, such as polyarthralgia, chronic fatigue, short-term memory loss, sleep difficulties, headaches, intermittent fevers, skin rashes, diarhea, vision problems, nausea, breathing and heart and other problems. Although there is not yet a case definition for GWI, the signs and symptoms loosely fit those found in CFS and FMS1.
Using the techniques of nucleoprotein gene trapping (NGT) that utilises nuclei-isolated nucleoproteins for probing with unique cDNA sequences and forensic polymerase chain reaction-hybridisation (FPCR) ~45% (NGT) and ~55% (FPCR) of 200 GWI patients and their immediate symptomatic family members who have GWI signs and symptoms showed evidence of mycoplasmal infections inside their blood leucocytes, but not in their blood plasma or serum. The most common species found was M. fermentans. In contrast, in nondeployed, healthy adults the incidence of mycoplasma-positive tests were ~6% (4/62).
Mycoplasma-positive cases of GWI have been successfully treated with multiple 6-week cycles of antibiotics2,3: doxycycline (200-300 mg/d), ciprofloxacin (1500mg/d), azithromycin (500mg/d) or clarithromycin (800 mg/d) plus nutritional support3. All patients on antibiotic therapy (n=87) relapsed within weeks after the first cycle of therapy, but after up to 6 cycles of therapy 69/87 recovered and 18/87 are still undergoing therapy. GWI patients who recovered from their illness after several (3-7) 6-week cycles of antibiotic therapy were rested for evidence of mycoplasmal infections and were found to have reverted to a mycoplasma-negative phenotype4,5.
The results were compared to 203 patients with CFS or FMS and 100 patients with RA. Using PCR 144/203 CFS/FMS patients were positive for mycoplasmal infections (60%), whereas only 3/32 healthy controls were positive. In mycoplasma-positive CFS/FMS patients we found a variety of mycoplasma species6. RA patients also had high frequencies of mycoplasmal infections (~45%), and these patients also had various species of mycoplasmas in their blood leukocyte fractions7.
We conclude that subsets of GWI, CFS (ME), FMS and RA patients have mycoplasmal and possibly other transmittable chronic bacterial and viral infections, and treatment of these chronic patients with appropriate antibiotics can result in slow recovery from their conditions4-6.
We propose that GWI is to a large degree due to multiple exposures to chemical, radiological and biological agents that cause multifactorial illnesses, some of which are transmittable to immediate family members and involve chronic infections8. Civilians with CFS, FMS or RA also often show the presence of chronic bacterial infections (mycoplasmas and others), and these patients can be successfully treated similar to the GWI patients with long-term antibiotics and nutritional support3.
Abhijit Chaudhuri, DM, MD, MB, BS, MRCP (UK)
Clinical Lecturer, Dept of Neurology, University of Glasgow and Dept of
Neurology, Institute of Neurological Sciences, Southern General Hospital,
Glasgow, G51 4TF
Chronic Fatigue Syndrome (CFS) is a common disorder that is characterised by fluctuating symptoms of fatigue, confusion, anomia, impaired concentration and musculoskeletal symptoms. Additional common symptoms include migraine-like headache, paroxysmal chest pain and hemisensory symptoms. Many of these symptoms including the severity of fatigue may be periodic, fluctuant and induced by physical and mental activities, stress and drugs or toxins. The fatigue in CFS is very similar to that found in disorders of the central nervous system such as Parkinson's disease (PD), Alzheimer's disease, multiple system atrophy and multiple sclerosis (MS).
Although fatigue is common in depression, CFS patients differ from patients with major depression in their clinical profile, steroid metabolism and response to standard antidepressant drug therapy. Current evidence strongly suggests that abnormal central neurotransmitter balance affecting monoamine metabolism, particularly dopamine, may play an important role in fatigue mechanism. In addition, changes in the neuronal ion channel function from time to time offers a rational basis to explain fluctuating fatigue and related symptoms in CFS. Ion channel abnormality leading to selective neuronal instability and altered neurochemical sensitivity may be the fundamental disease mechanism in CFS similar to other paroxysmal disorders affecting brain function such as migraine and epilepsy.
W. John Martin, MB, BS, PhD.
Centre for Complex Infectious Diseases, City of Angel Medical Center, Los Angeles, California 90026
The term stealth has been used to define a molecularly heterogeneous grouping of atypically structured cytopathic viruses that can induce multi-system illnesses in both humans and animals, without evoking an antiviral inflammatory response. A prototype stealth virus has a fragmented, genetically unstable genome, much of which is unequivocally derived from an African green monkey simian cytomegalovirus (SCMV).
Genetic sequences coding for the major cytomegaloviral antigens recognized by cytotoxic T cells are lacking in this virus isolate. Multisystem stealth virus infections with encephalopathy (MSVIE) can present clinically as a spectrum of neurological disorders, including autism, attention deficit and behavioural problems in children, and depression, chronic fatigue, fibromyalgia and severe motor, sensory and cognitive diseases in adults.
Widespread illnesses involving multiple family members and whole communities can be attributed to the spread of stealth viral infections.
Histopathological and electron microscopic findings in brain biopsies of severely affected individuals corroborate the vacuolating cytopathic effects (CPE) that develop in stealth virus cultures. Similar changes can also be induced in the brain and in other tissues of stealth virus-inoculated animals.
Foreign genes can be incorporated into replicating stealth viruses through genetic recombination. The identification of potentially oncogenic cellular sequences adjacent to SCMV sequences in the prototype stealth virus has raised the prospect that oncogenic stealth viruses may have emerged.
The City of Angels Medical Center is a new hospital facility in Los Angeles that will allow for an expanded program for the culturing and molecular characterization of stealth virus isolates. This will help expedite studies to determine the origins of stealth viruses and their associated genes, and also to establish the modes of virus replication and transmission. More importantly, it will provide a clinical base to evaluate various therapies aimed at suppressing stealth viral infections, and at repairing the cellular metabolic derangement caused by these viruses.
Information concerning CCID's programs within the City of Angels
Medical Center, including progress towards developing Epione as a
therapeutic option, will be periodically updated on the web site
Dr C.L. Jadin MD MBBCH
PO Box 4417 Randburg 2125, South Africa
Extensive research on rickettsioses has taken place over the last 6 decades by French, Polish and Russian scientist, following the lead of Prof Charles Nicolle (Institute Pasteur). They have published their research in detail, but unfortunately only in French. The fairly recently recognised syndrome, CFS, (the first occurrence of which was discovered in Nevada1, as was RMSF2) has given us a perfect opportunity to build on these scientists' research.
The diversity of symptoms displayed by CFS, fibromyalgia, rheumatoid arthritis and neurological dysfunction sufferers is as confusing as the diversity of symptoms of CRI (chronic rickettsial infection)3.
Diagnosis of CRI is established by the Giroud micro-agglutination test (Prof Giroud;, Pasteur Institute) against 5 different antigens: R. Prowazeki, R. Mooseri, R. Conori, R. Burnetti and neo rickettsia chlamydia 18. As well as this test, we find the following blood tests most relevant: liver function, thyroid antibodies, CPR, RF, ANF, mycoplasma (after the Manly Congress 1998).
The patients' syndromes most commonly exhibited are tiredness, myalgia, arthralgia, headaches, memory and concentration problems, psychological and neurological disorders, vision abnormalities, nausea, dizziness, loss of balance, recurrent sore throat, bruising, sweats, Raynaud syndrome. The physical examination often shows an inflamed throat, multiple adenopathies, heart abnormalities, RIF tenderness.
Since January 1991, 3,800 patients have been treated with a 7 days/month regime of tetracyclines plus adjuvants and exercises. The tetracyclines' dosages are high2, 4-7. They are alternated5-7, and combined6, 8, with macrolides, metronidazole and quinolones. The treatment takes from 6 months to 3 years3-5, 7, 8, 10, 11. The success rate is very satisfactory as reported in Manly last year; no toxicity has been reported and after the first three months the treatment is generally well tolerated.
Dr Philippe Bottero
Faculté de Medecine, Paris, France
Because-all the patients I have seen since 1981 had a sera reaction positive for rickettsia and chlamydia using the micro-agglutination on blade technique of P and ML Giroud (MAG) by Prof. J.B. Jadin of Antwerp, Belgium with special antigens cultured on guinea pig lungs and chicken embryos.
The great majority of the two groups' patients had vascular problems, both peripheral and central. After Ricketts and Charles Nicolle many writers have shown the clinical and epidemiological importance of the long survival of rickettsia in the reticular endothelial system, the walls of blood vessels and their secretion of vasoconstrictive toxins (GW58).
Since World War II many workers have reported that rickettsia and chlamydia are involved in chronic psychopathologies and have noted concomitant problems of a vascular type (LM61, LM62 and MAS63).
In Palermo (Italy) in 1987, I presented a paper (BOT87) reporting 60 differing cases of "psychopathologies" (with many CFS) treated with antibiotic regimes and associated with rickettsia and chlamydia and circulatory and other problems.
Group one (98 CFS): women, 78; men, 20; ages of the group, 15 to more than 60 years; for 67 cases the onset of symptoms was more than 2 years previously.
Group two (59 psychosomatic cases; 5 schizophrenia; 3 borderline; 10 children with aggresivity, excitement; 1 autistic child, 1 delerium with relapses. The ages of the group, less than 15 to more than 60 years.
We have shown that rickettsia and chlamydia are probably causative factors in many "psychopathologies". Sometimes associated with other intracellular bacteria (Prof. Nicolson, CA Mycoplasma and CFS) and viral agents becoming reciprocally active and perhaps predetermining genetic factors, and with initial stress which is often observed.
Examples of perjorative associations; mycoplasma and AIDS (Lo, Montagnier); hepatitis B and the agent delta; Burkitt's lymphoma.
Dr Bernie Hudson
Microbiology and Infectious Diseases, Royal North Shore Hospital, St Leonards, Sydney, 2065 Australia
Chronic fatigue syndrome (CFS) is diagnosed after a number of medical conditions including active, relapsing or untreated infection are excluded. The eventual outcome of infection with any agent is determined by the host immune response to that agent. Symptoms caused by active infection may be indistinguishable from those due to persistent harmful immune responses, despite eradication of the infectious agent. The Center for Disease Control and Prevention (CDC) criteria list a number of infectious diseases that must be excluded in order to diagnose CFS. Whilst this seems straightforward, it definitely is not. Confounding factors which will be discussed include the following:
All these factors require consideration in attempting to exclude possible treatable infectious causes of the individual's illness.
Melbourne Forensic & Diagnostic Services, Albert Street Medical Centre, 372-376 Albert St, East Melbourne, VIC 3002 Australia
Mycoplasmas are the smallest free-living organisms known and are distinguished by the absence of a rigid cell wall. There have been 16 species isolated from humans, six of which have the urogenital tract as the main colonisation site and eight of which have the oro-respiratory tract. Interestingly all have different pathogenic potential in humans, some of which have no pathogenic effect and some which are definitely pathogenic.
The most controversial of these species is Mycoplasma fermentans. First isolated in 1952, it has been reported in high incidence in chronic diseases involving abnormal states of the immune system. However, its pathogenic potential is still undecided. In vitro, it has been demonstrated to induce cytokine levels when infected in white blood cells, cause stem cells to turn tumorous, and allow dormant viral infections to activate and replicate at abnormal levels. Recently, M. fermentans membrane-bound proteins have been characterized and have been demonstrated to have monocyte/macrophage activator activity, but their role in disease causation or propagation have yet to be reported.
The aim of our research was to study the presence of M. fermentans in patients with CFS (which is considered a chronic illness involving the immune system) and the possible role of the monocyte/macrophage activator membrane-bound proteins.
Using a sensitive PCR procedure for determination of mycoplasma species DNA, serology, and RT-PCR for expression of M, fermentans monocyte/macrophage activator proteins, M. fermentans DNA was found in a significantly higher portion in the buffy coat layer from patients with CFS (45% of 195) than from asymptomatic individuals (14% of 104). When M. fermentans DNA load was measured it was found to be significantly higher in CFS than in asymptomatic M. fermentans-positive individuals. Interestingly, M. fermentans IgG serology only slightly correlated with differences in the two disease groups.
When M. fermentans monocyte/macrophage activator protein expression was performed from RNA isolated from buffy coat layers of peripheral blood, a striking pattern of differentiation was observed in CFS individuals as compared to asymptomatic individuals. This pattern of expression was only seen in the buffy coat layer of CFS individuals and correlated with increased serum levels of IL-6 and IL-12.
We believe that the expression of M. fermentans monocyte/macrophage activator proteins may be a most useful clinical marker for detecting M. fermentans pathogenicity in chronic illnesses such as CFS.
John Berrill: Partner, Maurice Blackburn & Co Solicitors
Exclusively practises in superannuation and insurance
Simon R. Molesworth AM, QC
In this paper the author examines the processes of investigation and research into Chronic Fatigue Syndrome and arrives at very disturbing conclusions. The author, as a Queens Counsel with a practice specialising in the fields of environmental, natural resource and planning law, expects, indeed requires for success in his practice, an approach to forensic investigation within scientific disciplines which is "open minded" to a multiplicity of theories and approaches whatever the problem or challenge might be. Benefiting from working with multi-disciplinary teams throughout his professional career, the author believes his observations reveal, by comparison, a generally inadequate response by the medical profession when faced with a patient presenting with CFS. More than just deserving criticism, the author believes many in the medical profession are leaving themselves seriously vulnerable to law suits when it is established that they were all too ready to dismiss CFS as a somatisation disorder or other manifestation of psychopathology.
In contrast to his experience and expectation, the author has found that all too often those in the medical profession associated with the treatment of CFS patients take the easy option of not pursuing on-going investigation of possible causes and monitoring of patients. He surmises that this response may be largely due to the influence of those encouraging a psychiatric diagnosis. Being aware of the controversial debates between those who favour an interpretation of the illness as being psychiatric in derivation and those who favour a physiological explanation, many in the medical profession consider the illness too difficult to continue investigation but rather entirely assign themselves to tackling secondary responses to the primary illness. So where depression in a patient is identified it inevitably becomes the prime focus, with little or no effort being assigned to continuing the investigation of any possible physiological causes or answers.
The current favour given to cognitive behaviour therapy involving treatment, by suggestive counselling and/or psychotropic medicine, aimed at assisting the CFS patient to address negative behaviour and cognitions which are presumed to exist and prevent the patient recovering, biases the treatment of such patients. The author observes that while patients are undergoing such therapy there is little chance of patients obtaining the potential benefit of other investigative work which accepts that there might be a physiological trigger or cause. Even in circumstances where multi-disciplinary teams are involved, observation seems to confirm that inevitably the therapist or psychiatrist dominates the chosen strategies presumably arguing that the absence of any certainty with respect to the physical manifestations of the illness warrants therapy primarily focussing on cognitive behaviour.
In these litigious times, the author observes such an approach to CFS treatment is perilous and could lead to a spate of litigation for both misfeasance and nonfeasance. In that cognitive behavioural therapy can have the consequence of the patient continually battling to establish credibility, that they are actually physically ill, one repercussion might be to exacerbate, indeed inflame, the patient's secondary depression response. If such treatment causes such consequences, the patient's continuing, indeed worsening suffering, gives rise to the spectre of misfeasance. In a related manner, the all too frequently observed avoidance of on-going physical monitoring and investigative examination of a patient, due to their assignment to the therapist or psychiatrist, gives rise to the very real prospect of nonfeasance. If doctors fail to continually monitor their CFS patients and compare notes from one to the other and generally exchange data, in short continually keep an investigative eye out for the illusive cause or remedy, then they are vulnerable if it is subsequently proven that by maintaining a pro-active forensic approach the patient might have found relief earlier.
Borrowing from his years of formulating and working within environmental management theory, the author rhetorically asks why the "precautionary principle" is not a code of practice embraced by the medical profession working with CFS. All options must be kept open, approaches which might shut out some explanations for the illness ought be avoided. The too easy dismissal of possibilities on the basis that conclusive scientific evidence is not yet established has the consequence of narrowing the parameters of research. As a lay observer, the author concludes, by way of an overview of current world-wide research into CFS, that there are more than enough indicators that physiological causes or triggers are likely to be soon established and that the illness will be confirmed as having a multiplicity of physical symptoms. When such breakthroughs are made, it will probably also be confirmed that distressing psychological effects are a frequent secondary association of the illness.
In concluding the paper, the author calls for the establishment of a nationwide non-exclusionary comprehensive register of all persons diagnosed with CFS together with all those who claim to have the illness. The register will record as much information as possible regarding all aspects of each patient's illness and treatment. Accepting that such a register may record people not properly categorised with CFS, the author nevertheless concludes that researchers ought never complain about too much information or too great a sample when to date lack of large scale investigation has probably prevented finding case history similarities earlier and extrapolating.
K. De Meirleir1, I. Campine*, P. De Becker, E. Van Steenberge1, C. Bisbal2, T. Salehzada2, B. Lebleu2, C.V. Herst1.
1 Dept of Human Physiology, Free University of Brussels, Brussels,
Supported by grants from ARC and the CFIDS Association to Bernard Lebleu.
Richard Schloeffel MBBS, FRACGP, FAMAS, Dip Acup (China)
Suite 2, 802 Pacific Highway, Gordon 2072
1/ Female, age 20: diagnosed with post-glandular fever CFS 5 years ago. Developed severe hyperemesis, constipation, bilateral eyelid ptosis, sleep and cognitive dysfunction, tachycardia and myalgia. Recently diagnosed with Mycoplasma fermentan, PCR DNA positive. Also found to have a severely delayed gastric emptying time but rapid bowel transit. Refractory to numerous therapies, with two hospital admissions for naso-duodenal feeding due to severe weight loss. Appeared to relapse further with doxycycline therapy for the mycoplasma. Currently undergoing bowel bacterial flora replacement. Possible bacterial infection of the enteric flora is producing bacterial toxins causing gastroparesis and other CFS/neurological symptoms.
2/ Male, age 21: who travelled to Papua New Guinea in 1996 where he contracted a severe gastroenteritis with 25kg weight loss in 7 days. A diagnostic cause of this episode was not made. Continued to have relapses of GIT symptoms and developed CFS symptoms including headaches, postural hypotension, tachycardia, muscle and joint pains, cognitive and sleep dysfunction, severe fatigue and frustration. Previously a State-grade athlete. Fully investigated with no cause found except for positive Mycoplasma fermentan PCR DNA and thalossaemia minor.
He was commenced doxycycline 100mg tbd, nystatin 500,000 units ii bd for 6 weeks on and 2 weeks off cycles 2 months ago. Also on tryptanol 5mg i nocte, melatonin 3mg i nocte, digestive enzymes i tds, cytobifidus bacteria 1 tsp bd, vitamin B, C and zinc one daily, chromium 200µg i daily, selenium 50µg daily, Efamol marine 1100mg ii bd, vitamin E 500mg i daily, co-enzyme Q10 10mg i daily.
Currently improving with no headaches, normal sleep, less muscular pain, less fatigue and only occasional GIT symptoms.
Dr M.G. King, PhD, M.Sc., M.A.P.S.
Sociologist Emile Durkheim last century named "neurasthenia" as an important cause of suicide. Chronic fatigue syndrome (the 1990s label for neurasthenia) has been totally overlooked as a suicide risk factor in the 1990s. Professional, and particularly medical, training programs dealing with youth suicide prevention fail to mention CFS as a risk factor. Furthermore there is a recent trend in medical practice to replace the diagnosis of CFS with the label of clinical depression.
It is argued that fashions and trends in diagnosis do not change these three clinical facts:
Dr R. Burnet, Prof. G. Scroop, Dr B. Chatterton, Dr Bu Yeap
Endocrine Unit, Royal Adelaide Hospital, North Terrace, Adelaide SA 5000
Chronic fatigue syndrome (CFS) is characterised by long standing debilitating fatigue, the pathophysiology of which remains undefined.
The effects of exercise on the hypothalamic-pituitary-adrenal axis, growth hormone, prolactin and plasma electrolytes in patients and healthy matched controls were studied. Subjects were each exercised for 10 minutes on a cycle ergometer at a work load of 75% maximal oxygen consumption.
Serial measurements were taken at one minute intervals for 10 minutes and 5 minutes thereafter for 70 minutes for plasma ACTH, growth hormone, prolactin, cortisol, sodium, potassium and bicarbonate ate rest, during exercise and recovery.
Resting values for serum electrolytes, growth hormone, prolactin and cortisol was similar in both groups.
A significant increase in the levels of ACTH was noted at rest in CFS subjects. During exercise the mean increase in ACTH in CFS was 86.6 ng/L compared to 54.6 ng/L in controls and although cortisol's values increased in both groups, the difference was nonsignificant. Maximum increase in potassium with exercise in CFS was 0.63 mmol/L and 0.98 mmol/L in controls (p=0.013). Plasma bicarbonate decreased by a mean of 9.5mmols/L in CFS and 8.5 mmol/L in controls (p > 0.05). The response to exercise of growth hormone and prolactin was similar in controls and CFS subjects.
These findings suggest an abnormal potassium response to exercise in CFS subjects. This decrease in potassium levels indicates either an abnormal and reduced flux of potassium across the cell membrane with exercise or a decrease in the total body potassium (TBK). Other studies have shown a decrease in the TBK, so this abnormal potassium response is likely to be due to a total body potassium deficiency.
There is no abnormality of the pituitary hormonal response in CFS subjects to exercise, but a diminished adrenal response to ACTH as seen in persons with any chronic debilitating illness.
Phillip Clifton Bligh2, Suzanne Niblett1, Leigh Hoskin2, R Hugh Dunstan1, Greg Fulcher2, Neil McGregor1,4, Julie Dunsmore3, Timothy K Roberts1, Henry L Butt1, Katrina King1, Iven Klineberg4
1 Collaborative Pain Research Unit, Bioanalytical Research Group, Dept
of Biological Sciences, University of Newcastle, Callaghan, NSW 2308
Chronic fatigue syndrome is defined as a disorder in which the subject has unexplained prolonged fatigue, often worse after minimal exercise, frequently associated with impaired sleeping, painful muscles, intermittently swollen lymph glands and impaired cognitive function. The pathogenesis has eluded explanation. The bioanalytical research group of the University of Newcastle has developed methodology for examining excretion of amino acids and organic acids into the urine. In collaboration with the Department of Endocrinology at the Royal North Shore Hospital, the overnight urine excretion rate of a number of amino acids and organic acids was measured in 100 patients with chronic fatigue syndrome, and in 83 age- and sex-matched normal controls.
The excretion rate of the metabolites was measured in units/minute. The most striking differences between patients with chronic fatigue syndrome and controls was a reduction in urine asparagine (p<0.0001) and a reduction in urine succinic acid (p<0.0003) in patients with chronic fatigue syndrome.
The excretion of urinary asparagine and succinic acid was highly correlated (p<0.00001). Urinary tyrosine (p<0.04) and urinary 3-methyl histidine (p<0.03) were significantly increased in patients with chronic fatigue syndrome. The urinary excretion of tyrosine, a protein catabolism marker, was associated with symptoms of fatigue, muscle pain, lymph node pain and cognitive disturbance.
The overnight excretion of succinic acid was correlated with the fasting plasma glucose (p<0.002). It is not known at present whether urine excretion rates of succinic acid and asparagine are correlated with serum concentrations of these metabolites or whether renal tubular function independently influences the urine excretion rates, and if so, whether renal tubular function is itself altered in chronic fatigue syndrome.
It is possible that urine asparagine excretion rates are low because of reduced entry of asparagine into the circulation, and thence into the urine. If the rate of entry of asparagine into the circulation is reduced, this could come about because of more rapid metabolism of asparagine in cells or because total body stores of asparagine are depleted. Further work is necessary to define these issues.
Neil McGregor1, High Dunstan1, Henry Butt1, Tim Roberts1, Iven Klineberg1, Phillip Clifton-Bligh2, Greg Fulcher2, Julie Dunemore2, Leigh Hoskin2
1 Collaborative Pain Research Unit (CPRU) Universities of Newcastle and
Chronic pain is one of the major reasons for seeking medical treatment, however the mechanisms by which chronic pain occurs are very poorly understood. Onset of chronic pain has been associated with infectious events, trauma and increasing life stresses, each of which may induce an increased host energy demand suggesting that dysregulation of protein turnover is associated with chronic pain. The data from three studies will be presented that assess the potential mechanisms of chronic pain seen in chronic polysymptomatic patients.
The metabolic events associated with chronic pain are distinct from those associated with chronic fatigue. The three studies show that alteration in the tyrosine:leucine ratio, a marker of the relationship between proteolysis and protein synthesis, is strongly associated with chronic muscle pain. Enhanced proteolysis is associated with diuresis and an increase in the secretion of excitatory amino acids, such as glutamic and aspartic acids. Prolonged muscle pain is associated with increases in ALT, AST, urea-markers of tissue damage.
These data support an alteration in nitric oxide production and enhanced NMDA activation, two factors essential for the initiation of spinal column hyperalgesia. The inhibition of these responses is mediated by noradrenaline and the opioids, and may explain why certain tricyclic antidepressants may be useful in management of the pain response. Understanding of the mechanism behind chronic pain is essential for the development of appropriate therapies.
The Adelaide Brisbane Serendipity Syndrome (ABS Syndrome)
A. Breck McKay1, John Whiting2, Aileen Jefferis3, Linda Bennetts3, Jacqueline M. McKay3, M. Sarah-Jane McKay4.
1 Family Physician, PO Box 353, Carina, QLD
What is the ABS syndrome? Simply it is the relationship between the effects of:
Paice E (1995) "Reflex Sympathetic Dystrophy" BMJ 310: 1645-1648
Aspinall U (1993) "Clinical Implications of Iliopsoas Dysfunction" J of Manual & Manipulative Therapy 1(2): 41-46
Jefferis A S (1996) "Front to Back" Jefferis A S, Adelaide ISBN 0 646 24827 8
Travell J G and Simons D G (1992) "Mycofascial Pain and Dysfunction" (Vol 2 The Lower Limb) in "The Trigger Point Manual", Williams & Wilkins, Baltimore
Cooper R G, St Claire Forbes W, Jayson I V (1992) "Radiographic Demonstration of Paraspinal Muscle Wasting in Patients with Chronic Back Pain" Br J of Rheumatology 31: 389-394
Chronic fatigue syndrome or CFS is known to be closely associated with excessive levels of citric acid excreted in the urine. This is usually thought to be merely a symptom of CFS.
What if elevated citric acid is not just a symptom of a dysfunctional Krebs cycle? This paper explores this question by starting with a presumption of severely elevated citric acid, and explores the biochemical consequences. The prediction is that hypercitricemia initiates a cascade of abnormally elevated or suppressed biochemical pathways and feedback effects that result in chronic tissue hypoxia.
Severe hypercitricemia is shown to cause abnormalities in levels of most amino acids (especially glycine) and problems with insulin, adenosine, uric acid and homocysteine metabolism. Post-arachidonic acid eicosanoids and nitric oxide synthesis are upregulated, causing further problems in the disorder. Disruption to cell membranes is expected. The theory also predicts that hypercitricemia is accompanied by mild hemopathic hemolytic anemia.
Treatment of hypercitricemia promises to be simple and effective if the inherent contraindications from the affected metabolic pathways can be overcome.
Keywords: chronic fatigue syndrome, hypercitricemia, citric acid cycle, glycolysis, phosphofructokinase, 2,3 bisphosphoglycerate, glycogen storage disorder, adaption to hypoxia, hemopathic hemolytic anemia, glycine, homocysteine, alanine, adenosine, uric acid, eicosanoids, nitric oxide.
P. De Becker, I. Campine, K. De Meirleir.
Human Physiology and Medicine
Furthermore, a physician gave a score from 0-3 (0 = absent, 1 = mild, 2
= moderate, 3 = severe) for following signs and symptoms:
K. De Meirleir, P. De Becker, C. Demanet, I. Campine and W. Vinken.
Human Physiology and Medicine
The immunophenotyping consisted of the following markers (both relative (5) and absolute (/mm3) numbers): CD2+ (E-rosette receptor), CD3+ (T cells), CD3+HLADR+ (activated T cells), CD25+ (activated T cells), CD4+ (helper/inducer T cells), CD4+CD45RA- (memory CD4-cells), CD4+CD45RA+ (virgin CD4-cells), CD8 (cytotoxic suppressor T cells), CD8+CD11b+ (suppressor cells/NK subset), CD8+CD11b- (cytotoxic T cells), CD19+ (B cells), CD19+CD5+ (CD5+ B cells), CD3-CD15CD56+ (NK cells), CD3+CD16CD56+ (subset cytotoxic T cells) and the CD4/CD8 ratio.
Statistical analysis was performed using the unpaired t-test.
P. De Becker, I. Campine, E. Joos, K. de Meirleir.
Human Physiology and Medicine
In order to develop a framework for determining physical impariment we will describe the results of our research on exercise capacity, use the American Medical Association guidelines for impairment rating of the respiratory system and use our results to develop an impairment rating system for CFS.
According to the AMA Guidelines for Impairment Rating (Table 1), female CFS patients have a degree of impairment of 30-45% which means a moderate impairment of the whole person; male CFS patients had a Class 2 impairment (mild impairment of the whole person). As expected the controls had no impairment.
P. De Becker, E. Joos, K. De Meirleir.
Human Physiology and Medicine
An individual rehabilitation program was designed for each patient. There were three different stages in the program:
Once a month the patients were seen by the physician in the hospital. The treatment period was 12 months; after 6 months and at the end of the study the patients again performed bicycle exercise test. During the study, no major changes of the medication were allowed.
The first 9 patients stopped the program because of practical problems and domestic commitments, the last 4 patients did not feel any improvement and refused to continue the program.
Patients who completed the 12 months exercise program were all subjectively feeling better although after 6 months they did not feel any improvement.
Maximal workload increased after 6 months and even more after 12 months. After 12 months also the maximal heart rate and work-output on submaximal level increased.
Although no normal level was reached, the slightest improvement in physical fitness parameters together with the other beneficial aspects of physical training are probably responsible for the subjective feeling of well being in the patients.
Motivation and close-monitoring of the patients (e.g. phone contact several times a week) could be very important to prevent drop-out.
K. De Meirleir, P. De Becker, I. Campine.
Human Physiology and Medicine
We analysed the data of 1210 consecutive patients complaining of chronic fatigue who visited our fatigue clinic at the Vrije Universiteit Brussel.
In this group, 752 patients fulfilled the CDC criteria for CFS (Fuduka, 1994). Of those CFS patients, 34 (4.5%) have a common factor in their past medical history that immediately preceded the onset of their CFS. These patients had received a blood transfusion a few days to a week prior to developing a 'flu-like syndrome that later proved to be the acute onset of their CFS. Another 8 patients also received a blood transfusion but their illness only started at least 2 months later, so that we cannot take these patients into our calculations.
None of these post-transfusion patients developed hepatitis C or other types of viral hepatitis. Some have antibodies (IgG) against CMV or EBV, but the development of these antibodies in time relationship to the blood transfusion could not be determined. In 9 of 34 patients the LMW RNaseL test was performed; in all 9 patients the low molecular RNaseL accounts for the upregulation of the total RNaseL enzyme activity. This 2-5A synthetase RNaseL pathway is activated in viral disorders.
These findings point towards a transmittable cause in this subset of CFS patients in which acute onset was temporally linked to blood transfusion. As viruses and possibly other micro-organisms seem to be able to trigger an acute onset of CFS and the fact that RNaseL dysfunction seems to be preferentially related to CFS, it comes as no real surprise that receivers of a blood transfusion, often being in a weakened health status, can develop CFS.
We therefore would advise CFS patients not to be blood donors and secondly that the administration of blood transfusions has to be very carefully considered and only be given when strictly necessary and not as a standard procedure after e.g. the delivery of a baby.
Bernhard Liedtke, Bill Paspaliaris
Melbourne Forensic & Diagnostic Services, Albert Street Medical Centre, 372-376 Albert Street, East Melbourne, Vic 3002 Australia
Coxiella burnetii is a rickettsi-like organism with a worldwide distribution and is the causative agent of Q fever. It can cause both acute and chronic diseases in humans. The disease is believed to be mainly asymptomatic and significantly under-disgnosed, due to its frequent confusion with non-specific viral illenesses. The disease can cause multiple organ damage, including endocarditis, which is sometimes fatal. Appropriate treatment with antibiotics usually leads to resolution. Q fever poses an occupational hazard to humans living in close contact with animals.
This study attempted to examine the prevalence of Q fever in Chronic Fatigue Syndrome (CFS). Guo Quan Zhang et al found that a 27 kDa outer membrane protein common to Coxiella species, when used with ELISA, is a sensitive and specific method for detecting anti-C. burnetti antibodies in human sera. A section of this 27-kDa outer membrane protein was synthesised and used in an ELISA test.
Thirty six CFS patients were tested with the following positive titres for IgG; 1 positive to 1:1600. Khin Khin Htwe et al reported positive Q fever results in controls worldwide averaging around 8 per cent. So far, this study has found positive results in 50 per cent of CFS patients.
The results suggest that circulating antibody levels to the causative agent of Q fever is higher in CFS than the general population. The contribution the infection makes to the symptoms of CFS is as yet unkown, however, symptoms of chronic Q fever (and other rickettsioses) are similar in many ways to CFS.
Guo Quan Zhang, et al (1998) Evaluation of a recombinant 27kDa outer membrane protein opf Coxiella burnetii as an immunodiagnostic reagent. Microbiol. Immunol. 42(6):423-428.
Khin Khin Htwe, et al (1993) Prevalence of Antibodies to Coxiella burnetii in Japan. J. Clin. Microbiol. 31(3):722-723
O.G. Baca and D.Q. Paretsky (1983) Q fever and Coxiella burnetii: a model for host-parasite interactions. Microbiol. Rev. 47(2):127-149
D Berg1, LH Berg1, J Couvaras2
1HEMEX Laboratories, 2IVF Phoenix
In 1994, the question was asked "Are recurrent miscarriages a result of an underlying hypercoagulable state?" From the data of a patient study of 25 women, the conclusion was that there is a hypercoagulable (HC) state in a subset of recurrent miscarriage patients. This led to the definition and understanding of the HOPI (Hypercoagulation Of Pregnancy & Infertility) Syndrome [BLOOD:11/97] or Immune Activation of Coagulation (IAC). The treatment for these women is subcutaneous (sc) heparin before conception and throughout the pregnancy. To date, there have been more than 150 successful first time deliveries from three IVF practices in Phoenix. Heparin reduces this hypercoagulable state and quiets some of the symptoms associated with an activated immune system. This treatment improves success rates from 25% to greater than 75%.
Heparin also reduces some of the immune mediated symptoms, including headache, pelvic pain, and fatigue. This finding suggested that this therapy would be useful in chronic fatigue (CFS) and fibromyalgia (FM). A review of HOPI patients from one clinic indicated that a subgroup indeed clinically fit the diagnosis of CFS or FM. To validate this observation, this study was begun to answer two questions: A) Is there an underlying hypercoagulable state in CFS and FM , & B) if so, would heparin therapy relieve the symptoms and / or normalize the patient?
Soluble Fibrin Monomer (SFM): SFM is a chromogenic assay based on the fact that SFM considerably enhances the conversion of plasminogen to plasmin by tPA. The amount of SFM is determined by measuring the amidolytic activity of plasmin on the chromogenic substrate S-2390. The release of p-nitroaniline (pNA) is determined at 405 nm. The concentration of SFM is plotted against absorbance and is linear from 0 - 100 nmol/L in plasma.
Clotting Kinetics (Sonoclot): The Sonoclot is an ex-vivo analog tracing of a whole blood clotting time. The tracing displays four actions of the coagulation process, consisting of activation of the cascade (ONSET), fibrin monomer formation (RATE), platelet function (peak of tracing) and clot retraction and fibrinolytic activity. The Sonoclot represents the current status of the coagulation system of the patient.
Platelet Activation Score (PA Score): The PA Score is the amount of platelet activation in the patient. The assay is either: 1) a platelet aggregation procedure, using 2.5uM ADP agonist and measuring the area under the curve, or 2) platelet expression of glycoproteins on the platelet surface as indicators of activation, using PAC-1 antibody against GP IIb/IIIa, CD62 (P Selectin from alpha granules being incorporated into the platelet membrane) and 10 uM ADP.
21 Female Patients: 9 CFS, 12 FM: See Table
1 test - 1 patient (5%)
2 tests - 5 patients (24%) - Suggested cutoff level
3 tests -12 patients (57%) for anticoagulant
4 tests - 3 patients (14%) therapy.
Abnormal Test Values:
Sonoclot Rate: 19/21 = 90%
SFM: 15/18 = 83%
PA Score: 14/21 = 67%
Fibrinogen: 11/21 = 52%
Improvement: CFS FM
None 0 0
Some 0 1
Moderate 4 7
Significant 5 4
See BD Lab Data as patient example of therapy and improvement.
The hypothesis that a subgroup of CFS/FM patients have a hypercoagulable state is proven by demonstrating thrombin (IIa) generation in these patients. Additionally, two out of three patients have platelet activation (PA).
Platelet activation reinforces thrombin generation, worsening patients symptoms. Aspirin (ASA) does not completely reduce this activation, which creates the "sticky platelet" syndrome. Even 325 mg of ASA twice a day may not attenuate this stimulation. Only removing the source of the immune activation (IgG) will turn off platelet activation. Activated platelets produce IL-1 and TNFa which can induce an inflammatory response in the patient. [When using heparin or coumadin, 81 mg ASA per day is used as an antiplatelet drug.]
To shut off thrombin generation, anticoagulant therapy is necessary until the underlying cause of thrombin generation is determined and removed. Anticoagulants can stop thrombin production while giving the body time to recover and down regulate the immune activation. The standard method for anticoagulation is to begin with sc heparin and follow with low dose coumadin, both on a weight adjusted basis. The goal is to normalize the patient from the hypercoagulable state. This is a lower dose than therapeutic anticoagulant regimens.
Soluble Fibrin Monomer (SFM) deposition is like a teflon coating on endothelial cells lining the capillaries and blocking passage of nutrients through to muscles, organs, etc. Simply shutting off the thrombin generation will allow the body's fibrinolytic system time to dissolve and remove any fibrin deposition on capillary surfaces.
The disease process occurs over time causing patient symptoms and it will take time to reverse this process to dissolve the SFM. Patients may not be free of symptoms for 1-3 months. Most have moderate to excellent recovery and remain symptom-free. Only one patient out of these twenty-one had minimal improvement in symptoms. Two patients needed an additional week of heparin therapy after converting to coumadin during their treatment.
This pilot study has shown:
A long term, placebo controlled study is beginning at this time. Only patients with abnormal baseline coagulation test values will be treated with anticoagulants.
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