This review will include information from:
- The Doctors Conference, Friday 26 February 1999,Manly Park Royal - Sydney Australia. 150 doctors attended and there were 16 presentations.
- The Open Meeting, Sat 27th February. About 400 patients and carers attended. This was officially opened by the NSW State Opposition Spokesperson for Health, Jillian Skinner, who spoke of the need for widespread recognition of the seriousness of CFS and the need for more access to sophisticated testing.
- The closed door Roundtable meeting on Thursday 25th February, this allowed time for more in-depth discussion. 30 doctors and scientists attended. I have sandwiched together speakers theory presentations with their treatment options, and Q's and A's directed at each speaker from all forums above. More general Q's and A's follow. Comments on patient work ups, and experiences from clinicians conclude the report.
Some words before I begin...I contracted glandular fever in 1980, age 14 and my health has not been the same since. I became much worse in 1984 when I contracted something else. I was severe with the illness from 1986-89 and can not begin to tell you the ignorance and arrogance I met with and the horror I went through. It is ten years on and that ignorance is still with us and it effects our lives in every way. I have edited our New Zealand ME magazine "Meeting Place", for the last 5 years, so there is not much I don't know about the misinformation, history, politics and confusion which surrounds this illness. One thing I want to impress upon you all from the outset, if you don't already realise, is that NOTHING about CFS is straightforward . Much of the science is in its infancy. Science is a slow process and it is slowed even further in CFS because much needed funding is continually being allocated into the psychiatric arena.
Some brief overall comments... If and how everything presented at this conference fits together is an unknown at present. To say CFS is complex is an understatement . It appears that subgroups are being teased out and treatment options are becoming available. The problem is sound testing, and appropriate treatment in each individual case. Getting that testing and treatment currently is the problem for patients all the world over. Many many thanks...to Christine Hunter (and her team of volunteers ) for her exceptional and continued commitment to those of us with this illness. Without her incredible tenacity this conference would never have come to fruition. Up until 5 weeks beforehand she had speakers coming but still didn't have enough funding. Thankfully Dame Elizabeth Murdoch AC DBE, made a significant contribution which enabled the conference to proceed. THAT is how tight these events run. We all have so much to thank her for. Support of the Foundation is vital for continued effective work and lobbying for better knowledge, treatment and understanding of this condition. The conference was a credit to the Foundation's aims, a Foundation that I wholeheartedly support. Please support the Foundation in whatever way you are able. I also wish to thank Prof Tim Roberts for his dedication and unflappable Ozzie style behind the microphone - he kept us all smiling.
by Simon Molesworth AM, QC, BA, LLB, FEIA, FAICD.
As a Queens Counsel in Environmental Law, Simon formally opened the conference and discussed his experience since his 10 yr old son became severely ill with CFS 4 years ago. The experience he could only describe as "horrifying". Being from a professional legal background, the nightmare of the CFS world - the ignorance of doctors, the contradictory literature, the lack of funding for research etc - was a shock.
He was disgusted to find the world over , that it is the patient groups that are having to support research and conferences and these people are so sick?. "Why the added burden?" he asked. The answer comes back to CREDIBILITY, a credibility that is being undermined by the pervasive and narrow views in psychiatry and in governments on the condition. The psychiatric single focussed approach he sees as a dangerous legal stance for a doctor to take with respect to this condition.(More on this later).
From his experience in Environmental Law and the change that has occurred over time at the government level in that sphere, he knows the way to get change has to be through a united effort. To gain credibility we need to stick together - sufferers, doctors that are dealing with the illness, CFS societies etc and we ALL have to pressure our governments.
He concluded by saying that the measure of success of all conferences are not necessarily the formal presentations, but the flow on effects for the future - in terms of contacts made, research collaborations set in motion, and the "in between" talking. And most of all ,the hope that comes from listening to those doctors who do understand, care, and have sound, sensible advice to offer.
Neurological Mechanism of CFS
by Abhijit Chaudhuri, DM, MD, MB, BS, MRCP (UK)
Dept of Neurology,
University of Glasgow,
Ref: Chaudhuri A, Behan P . Chronic Fatigue Syndrome is an Acquired Neurological Channelopathy. Hum Psychopharmacol. Clin. Exp. 14, 7-17 (1999)
Chaudhuri and Behan see CFS as a neurological illness, more common than MS or Epilepsy. They are looking for a theory that explains the underlying mechanism - that is how symptoms are generated and *why* they persist.
Any theory has to explain:
- The natural history - the onset characteristics (post infection, stress, immunisation, trauma , toxins, - they find a sort of double hit is described by most patients), the fluctuation of symptoms "the good day /bad day phenomena"
- The variety of symptoms - especially the unusual ones eg inability to tolerate normal doses of antidepressants, chemical sensitivities, alcohol intolerance, spasmodic hemi-sensory symptoms (paraethesia, numbness), heart rate irregularities and NMH, cravings especially of sweet things.
- Other tests/clinical abnormalities reported over the years - leukopenia, low steroid metabolism, serotonin sensitivity, chlonergic supersensitivity, abnormal blood brain flow, decreased intracellular carnitine, reduced total body potassium etc .
- The anatomical site dysfunction, especially of the brain - stem and perfusion problems AND the functional dysfunctions - neurochemical/neurohormonal defects (cytokine dysregulation, HPA axis dysfuction, cellular metabolic defects.
- How it might fit with theories of other CNS disorders.
What Chaudhuri presented was that all of the above could be understood via the mechanism of damaged cellular ion channels - or channelopathy. That is the fault lies at the cellular level. Ion channels or pores, are located all around a cells membrane. They control the ionic equilibrium of the cell, by taking in or expelling ions (eg Na+, K+). This is called ion exchange and is controlled in a finely tuned manner to maintain the cells structure/integrity and electrical activity.
If the pores get damaged (viruses and toxins can do this) then fluid exchange doesn't happen appropriately, the cell becomes electrically unstable (or 'excitable') and this disturbance has downstream effects - the cell can "stuff up" its other jobs eg providing energy for movement, producing hormones etc, because it spends too much energy trying to maintain itself because of the damaged pump. 'Excitable' cells overreact to stimuli, hence the sensitivity symptoms. They think it is the sodium/potassium pump (or channel) which is damaged in CFS. The cells involved being the nerves of the brain, heart, muscle and blood vessels.
They came to this conclusion by discovering that the Resting Energy Expenditure (REE) of cells (measured by indirect calorimetry) in CFS patients was increased compared with controls. That is, cells in CFS patients are using up energy at a much faster rate cf with controls. [In a normal cell 30% of the energy is used for maintaing the Na+/K+ pump]. They have also dicovered tha K+ is leaking from cells and this combined with the high REE suggests that the extra energy is being used to maintain the damaged Na+/K+ pump.
The key is that there are "reserves" in cells, and it is only when these reserves are over stepped that radical dysfunction occurs. This ebbing and flowing accounts for the fluctuation of symptoms and the variety of symptoms - different cells are "stuffing up" at different rates, dependent on their particular reserves. Other channelopathy disorders include, epilepsy, migraine and episodic ataxia - all of which have similar characteristics to CFS, many with CFS experience these disorders also.
Additionally, they have found that central neurotransmitter balance affecting monoamine metabolism, particularly dopamine, and suspect that this is playing an important role in fatigue symptoms. It is still early days in our understanding he concluded and emphasised the need for well controlled multi-centred trials. - 2 trials are underway.
Treatment Options: The need therapeutically is to stabilise the induced cell membrane "excitability" As patients do show serotonin deficiency, acetylcholine deficiency and dopamine deficiency, they currently use therapy to try to plug these areas mainly: tricyclics, antiepileptics and stimulants.
For trouble sleeping and smooth muscle effects, low dose Amitrip 10mg at night for protecting the brain -Antiepileptics - Carbamazepine and Lamotrigine for over sleeping, low dose Sertraline ( an MAOI, which has anticytokine activity) for fatigue - increase Dopamine using either dopamine agonists, stimulants, or MAOIs.
- Amantadine syrup, in brief short courses, 15mg in morning. The effects wear off, patient needs to learn to use it flexibly. If a patient comes off it too fast a 'rebound ' fatigue occurs.
- Amphetamines - dexedrine (he has longterm reservations)
- Ritalin (10-30mg day)
- Sertraline - Lustral (MAOI) . For safety reasons they use Sertraline.
In trial : an anticholinergic - Galantamine is in trial
In the future: Ion channel modifiers. Nicondinal (in progress) partial improvement in myalgia? Anticytokine drugs . MK869 is an antidepressent with anticytokine activity. Currently being used in the US for Arthritis, results good so far.
Substance P agonists, due for release later this year
He asked that we remember that antibiotics, if they improve symptoms, that it could be their anti-inflammatory effects (especially with macrolides), noting that asthmatics in the early '70s found relief with antibiotics.
Q. Is this ion channel damage irreversible?
A. The damage could be permanent, but the waxing and waning of the symptoms shows change is possible, therefore we should be able to manipulate the situation hopefully in the future.
Q. How is chemical sensitivity explained by your model?
A. The olfactory (nose) system is a very fast route to the limbic system, and the cells in the limbic system seem to have very excitable ion pores, therefore hyperreactivity is likely.
Q. Does this "excitability" of nerves possibly explain the paraesthesia (pins and needles) . This is often experienced whilst at rest after activity, when relaxed.
A. We think so. Transmission of a nerve impulse along fibres is conducted by use of the sodium channels . There is a precise mix of different types of channels - those that open and close quickly and those that open more slowly. When the sodium channels are inappropriately "excited" (damaged) as we see, the fast channels open and close faster giving a lopsided activation of bursts of activity in the nerve, which is felt as pins and needles. (Ed note: this mechanism is being studied in MS).
Stealth Viruses: Nature's Biological Weapons Program
by W. John Martin, MB, BS, PhD.
Centre for Complex Infectious Diseases,
City of Angels Medical Centre,
A stealth virus is an atypically structured virus, that can induce multisystem illness, but that cunningly can do so without evoking an antiviral anti-inflammatory, immune response in the host (the normal immune response).A virus normally triggers response from both arms of the immune system - the cellular immune system and the antibody immune system. In these viruses they do not evoke a cellular response because they aren't carrying the recognisable antigen in their genome (hence the term stealth). On electron microscopy they look herpes like in structure, and have foamy and vacuolating cytopathic effects.
Martin cultured the virus from the brain biopsy of a CFS patient in 1991. He believes these viruses cause encephalopathy and a spectrum of neurological disorders from Autism through to CFS , through to severe motor, sensory and cognitive disorders so far unclassified.
This year he has isolated the viral DNA and partially sequenced it. It appears to be a recombinant virus. Portions of it are related to human Cytomegalovirus (CMV). Portions are from the rhesus monkey CMV virus. Portions from the african simian green monkey CMV. More of it was monkey code than human. The crucial point is that CMV normally only causes infection in the species of origin. Also the virus lacks the genetic portion that invokes human cellular immunity. The polio vaccine (Salk) was cultured from African green monkey serum.
There was an illness outbreak in 1996 in the Mohave desert, which started off as a gastrointestinal sickness. There were 3 doctors in the area, the one female doctor and her 6 yr old child got it. Approximately 10% of the population became ill in some way. It included pets, and there were many unexplained deaths. The symptoms were variable. In children ADD became prevalent - the number of special ed teachers had to increase. Other diagnoses - autism, depression, FM, GWS, psychosis, CFS.
The child of the doctor became progressively worse. A neurologist, clinically could find nothing wrong. Had an MRI in April 1998 which John thought was very abnormal (signs weren't localising though). A brain biopsy was done and the biopsy went everywhere (Scripps Clinic, Mayo Clinic, Stanford etc). There was no coherent or agreed diagnosis from any of these clinics, all agreed cause unknown -death likely.
John did viral studies, found stealth viral particles, and recommended Gancyclovir treatment. After 2 weeks there was improvement 30%, now at school part-time. Gancyclovir Antiviral Treatment After this sentinel case, 200 patients who tested positive are being treated with Gancyclovir. Gancyclovir, is a second generation antiviral with high activity against CMV and Herpes viruses. Valtrex is not as effective.
The City of Angels Medical Center (address above) is a new facility for testing and evaluating various therapies (currently Gancyclovir) aimed at suppressing stealth virus infections, and repairing the cellular metabolic derangements caused by these viruses. Work in progress is on development of Epione as a treatment. He made the point that every patient has a right to know if they are virally infected.
For more information, and previous published studies etc, check http://www.ccid.org.
Q. Are you finding mycoplasma to be culturing with your stealth virus, could you be getting cross reactivity with your PCR probing?
A. No, we don't see mycoplasma in our cultures.
Mycoplasma in GWI, CFS, FM and RA Patients
by Prof Garth Nicholson
Institute for Molecular Medicine,
15162 Triton Lane,
Tel : +1 714 903 2900
Fax 1 714 379 2082
Refs : Nicholson (1996) J Occup. Environ. Med. 38, 14-16; Nicholson, GL Intern J Med (1998) 1: 115-117 and 123 -128
Nicholson et al Intern J Med (1998) 1: 80-92
Nicholson et al Biomed Therapy (1998) 16: 266-271
Haier et al Brit J Rheumatology (1999): in press.
Nicholson et al, Medical Sentinal (1999) : in press
Dr Nicholson discussed developments in his CFS - mycoplasma studies over the last 12months. He sees mycoplasma and other infections of the cell (eg rickettsia, chlamydia, brucella, borielia , coxiella) as a source of the morbidity in the illness. He doesn't know if they are causative , co- factors or opportunistic infections. He doesn't know whether the organism is relevant for each and every CFS sufferer, but believes the work may hold some answers for some people.
Mycoplasma are unusual as they have no cell walls and they act more like a virus than a bacteria. They can actually enter the cell and cause havoc with the cells metabolism - eg they can divert cellular energy (ATP) for their own use. They are also slow growing. When they exit from a cell they can also take bits with them eg membrane, giving rise to an autoimmune type response. The infection site of mycoplasma is inside the blood leucocytes (ie white blood cells), not in the blood plasma or serum. In the past, testing for mycoplasma was difficult because of this - no antibody response was formed. Two new technologies have been developed that test for the actual genetic material of the mycoplasma within the cell. These are called nucleoprotein gene tracking(NGT) and forensic polymerase chain reaction (FPCR). There are many species of mycoplasma, but all the species share some common genetic material.
Garth's studies were firstly with Gulf War Vets. Out of 575,000 troops deployed, approximately 15,000 are now dead. Many of their family members also came down with a similar illness. Of the tests done on the Vets only CD4/CD8 ratios were abnormal and NK cells showed immune problems, along with reactivation of EBV and HHV6.
Of 200 GW patients and their immediate sick family members 55% showed evidence of mycoplasma in blood leucocytes . Treatment of positive patients, has been successful, with multiple 6 week cycles of antibiotics. All patients relapsed (n=87) within weeks after the first cycle, but after up to 6 cycles 69/87 recovered and 18/87 are still on therapy. Recovered patients test negative to mycoplasma.
He is now teaching other labs how to do the testing and the US Department of Veteran Affairs has funded a huge study (US12 million $) at 28 military hospitals across the US , treating 2,000 sick veterans using 200mg doxycycline/day for 12 months.
In CFS, using FPCR, 144/203 were positive to mycoplasma (60%). In CFS the difference is that a much wider variety of mycoplasma species were found, about half the patients were multiply infected with between 1-6 species. The score of severity increased with multiple infections.
In one study treating 73 CFS patients, 37/73 recovered after 4 cycles, a further 21 after 6 cycles, and a further 14 after 8 cycles. The treatment recommendations for CFS have been modified over the last year.
If a patient tests positive then note:
Current Treatment Regimes for Mycoplasma Positive CFS Patients
- Therapy HAS to be prolonged, cutting it short does more harm than good.
- Dose of antibiotics are high and prolonged- this is so entry is made into the cells, because the organism is within the cell and therefore it has an inherent insensitivity to drugs. Pulse dosing is best (ie take all at once, don't split throughtout the day)
- Duration - he is now using antibiotics for 6 months without a break, then continuing with the 6 week on, 2 week off, cycles. In some patients, physicians are now using the antiviral Fanvir in the 2 week off period. He thinks this is probably better. Antibiotics used :Doxycycline 200-300mg/day, Ciprofoxacin (Ciproxin) 1500mg/day,Azithomycin (Zithromax) 500mg/day or Clarithromycin (Biaxin) 500mg/day.
- Herxheimer reaction very likely, IVis maybe the way to go in the early phase of treatment.
- Switching antibiotics is necessary because of mixed infections.
- Avoid sun exposure.
- Stay off sugar, alcohol, and decrease as many of your known allergens as possible.
- Recommended vitamins/ minerals / lactobacillus etc should be taken at a different time of day to the antibiotics. B complex should be given sublingual because of malabsorption problems. Vit C &E plus CoQ10. Selenium, Zinc, Chromium and magnesium.
- Hyperbaric oxygen has helped some patients [Mycoplasma like low oxygen conditions]
- Moderate exercise is good when possible
- Saunas are good, 2-3 times a week, 15-20 mins. This helps mobilise the infection as does exercise.
- Epsom salts plus peroxide baths is useful for muscle pain.
- At end of antibiotic therapy, various immune modulators have anecdotely helped patients eg. Whey Protein (by company called Immunocal), Noni Juice, Echinachea etc. NB. Recovery is slow and attention has to be made to rebuilding the immune system following treatments using antifungals where necessary and nutritional support. He notes that after therapy CFS patients become less chemically sensitive. He does not think the response is the immuno suppressive effects of the antibiotics. [Ed Note: If you are to embark on this therapy, be sure to have ALL available latest literature. The references above discuss the pros/cons of various antibiotics, and all doses of nutritional supplementation etc]
Q. How do we reconcile potential long term problems of prolonged antibiotic usage?
A. If you culture positive, treat, then its negative, the patient feels better, then its working, that's all we have to go on. Longterm effects - we just don't know.
Q How contagious do you think mycoplasma is?
A. In the military it took time before family members got ill. In CFS patients they have been sicker longer , have multiple infections and contagiousness is an unknown.
by Dr Cecile Jadin MD MBBCH.
P.O. Box 4417
Tel + 27 11 460 1670
Fax +27 11 460 0209
Cecile, originally from Belgium, a surgeon by profession, is now working in Sth Africa as a clinician. For the last 7 years, she has focused her research on Rickettsia. Her father, Professor JB Jadin, undertook groundbreaking research on Rickettsial infection, first in the Pasteur lnstitute of Tunisia, then in Central Africa with Professor Paul Giroud. From an early age she was familiar with the work of her father and colleagues. What she presented , therefore were the results of teamwork from the last 100 years.
Eight years ago, one of her friends became unable to walk and was diagnosed as having CFS. For 4 years Cecile suggested the diagnosis of Rickettsial infection. The Weil- Felix test was performed several times in South Africa and the results were negative. 4 years ago her friend came to her with an acute appendicitis. She removed her appendix, and upon her request, she sent her serum to her father to test for Rickettsia, via the Giroud's Micro-Agglutination testing and it was positive. Cecile treated her with Tetracyclines and 3 weeks later, she was riding her horse again. Cecile admitted she herself was sceptical. But this case brought her a couple of 100 patients and the publicity surrounding an investigation of her methodology by the South African Medical Council brought several thousand more.
Rickettsiae, like mycoplasma, are infections that are half way between bacteria and virus and they infect inside cells. Because they are related to bacteria, they are sensitive to antibiotics. The most well known is the strain R. Prowaseki which causes epidemic Typhus. Some strains are known to be capable of causing non-obvious infections which lead to symptoms under certain conditions.
Rickettsial-like organism could be involved in some CFS patients for many reasons because (to name a few):
- Onset is acute in many cases, with a flu like illness, but illness continues (Rickettsiae can infect then remain dormant until something activates them)
- The epidemic and non epidemic cases could highlight the life of a germ emerging and disappearing in a wave pattern, epidemically and historically. The survival of the germ being circumstance dependent - other factors are maybe needed to maintain itself in a particular host.
- Lymphocyte studies conducted on sheep with tick-borne diseases, CFS patients, and patients with Q Fever endocarditis are showing amazingly similar results.
- During the First World War, 25 million Russians contracted Louse- borne epidemic typhus, resulting in 3 million deaths. Why not before or after? It could suggest that the stress factor reactivates the virulence. In the medical history of CFS patients, stress has often been described as the start of the illness.
- The symptoms displayed by CFS, Fibromyalgia, RA, and even neurological patients like MS, show the same diversity of symptoms as known Rickettsial patients.
- The success rate of the Rickettsia treatment, Tetracycline. Dr Phillipe Bottero on 100 patients, Dr Peter Tableton on 300 patients and herself on a much larger number of patients -3,800. Patients maintain an 84% - to 96% recovery rate.
Three Cornerstones of Diagnosing Chronic Rickettsia Infection:
- By Giroud's Micro-Agglutination test against five strains of Rickettsia: R. Prowazeki,R. Mooseri, R. Gonori, Coxielia Burnetti, Neo Rickettsia , Chlamydia . Standard Rickettsia tests are only for acute infection.[This testing is only available in France and South Africa ]
- Blood tests, most relevant: - Liver Function Tests - Rickettsia can show hepotoxicity - Iron study - abnormalities sometimes. - Thyroid antibodies, rather than TFT, although the TFT show abnormalities in 3% of patients, the thyroid AB are elevated in 28% of cases and improve or normalise rapidly with treatment. - CRP, RF, ANF, WR elevated in 53% cases but improve with treatment
- Physical Exam Symptoms -tiredness, myalgia, arthralgia , headaches (retroorbital and temporal), memory and concentration deficit , psychological and neurological disorders, chest pain, palpitations, vision abnormalities, nausea, loss of balance, recurrent sore throat, bruising , sweats, low grade fever,Raynauds syndrome. A constant guideline in the Physical examination shows - An inflamed throat - Multiple adenopathies - Heart abnormalities (vascular and valvular impact ) - RIF (right inguinal fascia) tenderness (ie tenderness of the appendix region )
Treatment of Rickettsia
Treatment consists of 7 to 12 days per month of a specific Tetracycline used as follows :
- A high dosage is required 2g/day for about 12 days for the old tetracyclines and phenicolates with the usual reservations about chloramphenicol and 300 mg/day for doxycycline and 6 capsules per day for lymecycline(6) with the limitation of: - Safety Our experience is that when liver functions are normal to start with, they stay normal. If they were abnormal, they will improve during treatment and generally return to normal. Rickettsia are more hepotoxic than Tetracyclines. - Tolerance a) The gastric intolerance will be successfully prevented by using a gastric pump inhibitor during and if necessary before and after the administration of the Tetracyclines. b) The tolerance of the treatment is directly related to the J/Herxheimer reaction , a reactivation of old symptoms and/or exacerbation of present symptoms that occurs on antibiotic therapy. Its presence has a very important diagnostic and prognostic value. It will fade with the number of treatments received. When very severe, the H/R is treated with Probenecid.
- The Tetracyclines are alternated because:
a) A patient is frequently contaminated by many strains of Rickettsia and different Rickettsia have different sensitivity to different Tetracyclines.
b) A patient might build resistance to each Tetracycline .
c) Patients show individual sensitivity to different Tetracyclines or combinations and is very often a privileged reaction to a specific treatment.
- The Tetracyclines are combined with Quinolones, Macrolides or Metronidazole, because Rickettsia present a wide heterogeneity of susceptibility of different drugs
- The treatment is often long due to:
a) The chronicity of the germ
b) The multiple foci of Rickettsia
c) The fact that Rickettsia have a slow evolution and some foci are dormant, encapsulated and therefore protected from antibiotic therapy. Only when they become active can they be treated.
d) Each treatment will allow the immune system to produce and maintain a proper and efficient level of antibodies. This happens each time the antigen Rickettsia are released from the cell to the blood stream while on antibiotic therapy .
e) The length of the disease should logically imply a lengthy treatment. In our experience, this point is not always true. Patients, ill for many years, may recover after a few months treatment.
- Adjuvants such as Vitamin B complex and acidobacillus are also used.
- Cortisone is avoided as it reactivates the germ .
- Exercise is recommended, for the following 3 reasons: - Rickettsia is a vascular disease - The fact that strains of Rickettsia grow better in vitro when maintained in a C02 enriched atmosphere. - The suggestion that Rickettsia grow best when the metabolism of the host cell is low .
- Hot baths- to eliminate toxins produced by Rickettsia when liberated in the bloodstream .
- Reinfection may obviously occur. Reactivation (called so, rather than relapse) may also happen due to the interaction of bacteria, virus, stress, pollution, etc. causing the Rickettsia to change to active from dormant. Treatment Time Treatment is for 3 months to 2 years - 8 months on average. However, as previously mentioned, the length of treatment is not directly correlated to the length of illness. If symptoms return, treat, keep treating.It has also been reported that when patients stop treatment before all symptoms resolve, they slowly, over the following months, get a return to their level of symptoms that existed before treatment began. So treatment must not be stopped until all symptoms resolve and a negative testing is obtained. Patients can be divided into 2 categories:
1. Fast progress - their illness was mainly Rickettsia
2. Slow progress - their illness was Rickettsia plus other factors No toxicity has been reported after the first 3 months, treatment is generally well tolerated.
- Giroud P, et al. Au sujet de maladies rickettsiennes et de celles aux agents proches en Europe Occidentale. Extrait de Bulletin des Sýances. 1976; 3: 420-430.
- Giroud P, Jadin J. Conceptions actuelles concernant les rickettsioses et leurs vaccinations. Ann. Soc. Belge M«d. Trop. 1961;
- 193-206. 3. Le Gac P. Le traitement de la scl«rose en plaques d'origine rickettsienne et n«o-rickettsienne. Compte rendu des communications consacrees aux rickettsioses et neo-rickettsioses. 1986.
- Roca V. Transient acquired immunodeficiency during rickettsial disease. Arch Intern Med. 1984; 144: 198-99 (letter).
- Jadin J, et al. M«ningite ÷ m«ningocoques et rickettsioses. Archs Inst. Pasteur Tunis. 1987; 64(3): 321-325. 6 .Bottero PH. L'antibioth«rapie et ses adjuvants. Compte rendu des communications consacrees aux rickettsioses et neo-rickettsioses. 1986.
Rickettsia and Chlamydia in CFS Patients
Dr Philippe Bottero
Faculte de Medecine,
10 Avenue Henri Rochier
Tel +33 47 526 1576
Fax +33 47 526 3109
In an open study , since 1981, 98 CFS patients were all found to test positive for Rickettsia and Chlamydia using the Giroud micro agglutination test. The great majority of patients have vascular problems, both peripheral and central. Treatment : For a minimum of 6 months, using cyclines and or macrolides, together with vasodilatory medication, chloroquine and warm baths in the manner of Jadin. Results: 78/98 patients good and very good results, 4/98 fairly good, 16/98 didn't help.
CFS and Infectious Diseases
by Dr Bernie Hudson
Microbiology and Infectious Diseases,
Royal North Shore Hospital,
St Leonards 2065
The contention in this presentation was that whilst the CDC definition of CFS says we have to exclude a number of infectious diseases in order to make a diagnosis of CFS. In reality this not as straightforward as it would seem.
Symptoms caused by active infection may be indistinguishable from those due to persistent harmful immune responses, despite eradication of the infectious agent . The problem he finds are tests for active infections often have problems with false negative and false positive results. Confounding this is that some agents may not cause a detectable antibody response eg spirochetal infections such as leptospirosis, Lyme disease; some rickettsiosis and some arbovirus infections. Another additional problem is that current tests for many infections are unable to determine whether the infection has resolved, or whether it is persistent and causing illness eg Ross River, EBV, CMV,HHV6.
Testing is just not sensitive enough to rule out even the infectious diseases the CDC asks us to!! He finds all tests hopeless. Thus, he sees it as completely possible that untreated, undescribed or poorly characterised infectious disease could be causing some instances of the illness that is being called CFS, simply because testing isn't effective enough at present. An example of one of these infectious diseases is Lyme disease, which according to Dr Hudson is prevalent in Australia - despite what Government suggests. He has found 14 Lyme patients in 301 patients referred to him. He thinks the only reliable way to test is to culture directly from biopsy, especially with the Lyme spirochette, which is known to persist for longer than 10years. In patients where he thinks infections are involved he treats empirically with either Amoxil or Doxycycline for a month. If no response he assumes he is not dealing with Lyme.
Mycoplasma: Cause, Co-factor or Commensal in CFS
by Bill Paspaliaris
Melbourne Forensic and Diagnostic Services,
Albert Street Medical Centre,
372-376 Albert St,
Bill discussed the controversial status of mycoplasma since its pathogenic potential in medicine is still undecided. In test tube it has been demonstrated that that mycoplasma can induce increased cytokine levels when infected in white blood cells, and can allow dormant viral infections to activate and replicate at abnormal levels.
Recently, M. fermentans membrane-bound proteins have been characterised, and have been demonstrated to have monocyte/macrophage activator activity (RT-PCR). The aim of the study was to investigate whether this testing may have usefulness as a clinical marker.
Data was presented on 195 CFS patients , and 104 asympomatic controls who had testing for mycoplasma by PCR DNA testing, RT - PCR testing and Serology (ie titres) Tests were also done for IL-6 and IL-12 on positive patients
PCR DNA testing found 71/195 CFS patients were Mycoplasma (genus) positive (45%) , (45 were positive to M fermentans) . 14% of non symptomatic controls tested positive to mycoplasma (genus). When M. fermantans monocyte/macrohage activator protein testing (RT-PCR) was performed from RNA isolated from the buffy coat layers of the peripheral blood, the pattern of activity was striking. In 12 CFS patients tested, it correlated with increased serum levels of IL - 6 and IL -12. Serology (ie IgG titres) showed lack of sensitivity and no correlation with DNA probing or RT-PCR testing.
In conclusion he suggested that the test of expression of M. fermentans monocyte/macrophage activator protein may be a useful marker for detecting M.Fermentans pathogenicity (ie activity) in CFS. He thought that mycoplasma could well be inducing IL-6 and IL-12. [Ed note: There was much discussion on this, the outcome in my eye was that the best test is still to test for the DNA by PCR probing]
Superannuation and Iinsurance Issues for PWC's
by John Berrill
Partner, Maurice Blackburn and Co Solicitors and Member of the Chronic Illness Alliance Superannuation and Insurance Advice Service.
As a solicitor Mr Berrill outlined the problems that people with CFS have when claiming for superannuation or insurance. These problems include the recognition of CFS as an injury or illness, the problems in the assessment of the permanency of CFS, claims processing and appeal rights.
He noted that many people with CFS may be able to claim a lump sum or pension if they have any superannuation policies. The problem is people don't know that they can claim disability benefits from their superannuation or when they can get a payout of their contributions. You can usually make a claim at any time Even if you are on Social Security many should be able to make a lump sum claim. The crux of the issue for the insurer is 1) Is CFS a real disability & 2) Is it permanent If you are not sure whether you have disability benefits from your policy, ask for help
For Personal Insurance:
If you have a personal insurance policy - life insurance, income protection, loan insurance etc you may be able to claim disability benefits. Check the policies you have. Insurance disability claims can usually be made at any time - it is best to claim as soon as possible though. In both cases if you are able to return to work, there is nothing to stop you from doing so. If you have received a lump sum, you will not have to repay the lump sum.
There is a free advice service to help people with disabilities deal with these legal issues. The advice given is by volunteer lawyers and is free. Currently the Centre is only operating in Melbourne, it is hoped to open an advice centre in Sydney soon.
Contacts: John Berril 03 9345 2742, he will refer you onto a solicitor for free legal advice. If you want to write to the service with queries, please address it to:
The Superannuation and Insurance Advice Service
c/o GPO Box 523J Melbourne 3001 Australia
If you are in Melbourne. The Service is open every Thursday night between 6-8pm and is held at the Epilepsy Foundation, 818-824 Burke Road, Camberwell, and the MS Society, cnr Gordon & Barkly Streets, Footscray, every alternate week. Appointments can be made by calling: The Epilepsy Foundation (03) 98132866 or The MS Society (03) 9689 3999.
The Precautionary Principle
CFS Investigative Research and Patient Support Regimes in Litigious Times
by Simon Molesworth AM, QC, BA, LLB, FEIA, FAICD
As an outsider to medicine, but as a lawyer, Simon believes that not only is there an inadequate response by the medical profession to CFS but also that there are those in the medical profession who are leaving themselves vulnerable to law suits when it is established that they consider CFS as somatisation disorder or another manifestation of psychopathology without pursuing on-going investigation for other causes.
Time and time again he has found very sick people being sucked into the clutches of inappropriate people (both medical and alternative) because they are being short-changed by their doctors. In reality he has found that the psychiatric explanation and cognitive behavioural therapy is the ONLY message getting through to doctors and this is causing a biased, one-sided approach to the illness. Even in the circumstance where multidisciplinary teams are involved, observation confirms that inevitably the approach of therapy focuses on assumed inappropriate cognitions and the psychiatric approach - CBT plus psychotropic medicine, dominates.
Given that there are other well-published approaches BALANCE is urgently needed. Doctors have an obligation to get the learning out there, in all professions if you aren't up with the play then clients have the right of redress. The message HAS to be (given the literature) that CFS is a complex multifaceted illness, with a multiplicity of causes. Failure for doctors to recognise this raises the spectre of litigation.
Misfeasance could be applied where treatment worsens the patient's suffering. Nonfeasance applies where there is a lack of ongoing monitoring and investigation of all the options, if it is subsequently proven that a more proactive forensic approach may have brought relief earlier.
To date he has observed that monitoring is not happening and that patients are left in limbo land - this could be classified as nonfeasance. Based on his work in environmental law, Simon asks why "The Precautionary Principle" is not a code of practice embraced by the medical profession working in CFS? This principle suggests that ALL options must be kept open so the parameters of research are not narrowed by a particular discipline.
In conclusion, he called for the need for a nationwide non exclusionary comprehensive register of all persons diagnosed with CFS together with all those who claim to have the illness. Then we have data, then we have numbers, then we can gain some power. Also, the need for dedicated CFS clinics. His warning to doctors based on the changes in environmental law that he has seen over the past 10 years was "be warned" - he predicts litigation over this illness in upcoming years.
RNase-L Dysfunction Disorder in CFS
by Dr Kenny de Meirlier
Department of Human Physiology,
Free University of Brussels,
In collaboration with Bernard Lebleu ,
Institute of Molecular Genetics,
Worksponsored by the CFIDS Association of America.
Dr Kenny de Meirlier discussed the new LMW 37kDa RNaseL enzyme discovered to be active in the antiviral 2-5A pathway in at least a subset of patients with CFS. Normally in the antiviral pathway there are only 2 forms of RNaseL, one at 80kDa the other its breakdown product at 40kDa. RNaseL cleaves viruses and destabilises cell protein metabolism.
In patients with CFS the 2-5A pathway is activated, and RNaseL activity is increased. Suhadolnik showed at the AACFS conference in Boston that the 37kDa RNaseL is very stable and is not a breakdown product of 80kDa. He also demonstrated that it is has RNase activity because it can be inhibited by human RNaseL inhibitor. He also showed that it is very active in CFS patients - 6times more active than either 80kDa activity. The high activity likely a result of less binding sites.
At this conference Kenny presented 3 studies:
- Replication Study Kenny showed that he was able to utilise a different technique to Suhadolnik and find the same results. The technique he used is described by Charachon et al (Biochemistry 29 : 2550-2556, 1990). He showed that some patients show all 3 enzymes - the 80, 40 and 37kDa, but some show no 80, no 40 but only 37kDa. He also showed that the situation "flip/flops" dependent on how well the patient is doing ie they can go from a normal looking 80/40kDa situation to an only 37kDa situation in relapse. Out of 429 patients tested 95% showed evidence of the 37kDa enzyme, with over half the patients showing a 37/80kDa X 10 ratio great than 2.0.(note that 37kDa and 80kDa are NOT inversely related). Severity related to higher levels of the 37kDa. He concluded that the observations could provide the basis for the biochemical assay for the differential diagnosis of CFS and for follow up of its clinical evolution.
- Ampligen Follow Up 24 patients had been followed up 2-4 years after completing Ampligen therapy in open label fashion. At the time the 37kDa test was unavailable to guide therapy. 18 patients had been good responders, and 17 have remained well . For those that hadn't responded Kenny postulated that they may have needed more therapy or that they did not have the 37kDa problem in the first place.
- Recent Ampligen Trial 44 patients were treated with Ampilgen in open label fashion, mean illness duration was 8yrs, mean age 36yrs, 31/34 female. The first 4 doses were at 200mg, then 400mg 2X week. Initially all were treated for 4 months, some were then treated 6 months, some 9 months, some 15 months - dependent on response, and 37kDa activity measures. Neurocognitive improvement was seen from weeks 4-5. From week 16 on improvement was seen in cognitive deficit scores, Karnofsky scores, exercise capacity. There were no reported adverse effects.
Q. How does the 37kDa RNaseL fit in with other diseases?
A. The high activity of the 37Kda RNaseL is indicative of poor regulation in the antiviral pathway. The enzyme also plays a role in deregulating protein synthesis (as explored by Neil McGregor - Newcastle). In terms of other diseases, you don't find elevated levels of RNaseL in none infectious diseases eg. depression. It is induced by interferon and induction of interferon only occurs with infectious mainly viral illnesses. We are looking at MS and seeing activity there also in flares, we think the conditions are in some way related.
Q. Can bacteria induce RNaseL activity?
A .Not likely. It is likely solely related to viral disorders and reactivated viral disorders.
Q. Is their any hereditary information about the 37kDa?
A. If there is a any genetic problem it is likely at the level of being unable to produce appropriate inhibitor (RLI) .The enzyme itself is virally induced so it is unlikely to be accounted for genetically.
Q. Has the 37Kda been sequenced yet?
A. That is underway
Q. Is it possible that something else like Mycoplasma could be producing it?
A. It may be possible , but unlikely.
Q. Ampligen also induces interferon, how does this pan out in practice?
A. Ampligen has lots of actions and yes is does induce interferon and this is why I think we see patients increase in symptoms at the beginning of therapy. Ampligen is a non specific immune modulator.
Q. Who are the best candidates for Ampligen?
A. Our selection criteria at present are those positive for 37Kda RNaseL, who have been ill less than 5 years, and who are less than 50 years old. Most tend to be post mononucleosis.
Q. About HHV6A, is it's reactivation being controlled on Ampligen?
Q. What about getting Ampligen in Australia and New Zealand?
A. Everyone is waiting for approval from the FDA and EU equivalent.Once it gets approved then it is really up to lobby groups in your countries to make your governments make it available. That means talking to the parent company in South Africa.
CFS: Two Case Presentations
by Dr Richard Schloeffel MBBS, FRACGP, FAMAS, Dip Acup (China)
Suite 2, 802 Pacific Highway,
ph (02)9418 1388
fax (02) 9418 1418
Dr Schloeffel has been seeing CFS patients for the last 18 years and feels in the last year he has had more tools for management but still is at a loss as to what to do in many cases. He presented 2 of his severe cases which contrast and highlight the difficulty/crisis he finds himself in-
1. Female, age 20. Had Rubella vaccination and Glandular fever age 14, relapsing/remitting CFS course until March 1997. Since then she developed daily vomiting up to 25 times a day, constipation, bilateral eyelid ptosis, severe sleep and cognitive dysfunction, postural drop, severe weight loss because she can't keep food down. Has been refractory to numerous therapies. Has been hospitalised twice for naso-duodenal feeding. Nuclear medicine gastric emptying study indicated severe delayed gastric emptying, with rapid bowel transit. Recently diagnosed with Mycoplasma fermentans by PCR. He tried her on Doxycycline100mg/day , within 3 weeks she was much worse. Now is on naso-duodenal feeding. On the theory of possible bacterial infection of the enertic flora producing toxins causing gastroparesis and neurotoxic symptoms he has had her bowel flora replaced with her sisters. This has slightly reduced the vomiting - down to 5 times a day but he fears she could still likely die.
2. Male, age 21. who travelled to Papua New Guinea in 1996 where in contracted severe gastroenteritis with 25kg weight loss in 7 gays. A diagnostic cause of this episode was not made. Continued to have relapses of GIT symptoms (severe nausea, vomiting , bloating etc) and developed CFS symptoms including severe fatigue, headaches, postural hypotension, tachycardia, muscle /joint pains, couldn't sleep at all, and was completely FRUSTRATED, not depressed. He was 188cm tall and weighed only 63kg by this stage. His tongue was heavily coated. His memory was hopeless and his mother had to bring him into the surgery. He was a former State grade athlete - high jumper.
He was fully investigated with no cause found except was positive for Mycoplasma fermentans by PCR DNA testing and thalossaemia minor. Two months ago he was commenced on doxycycline 100mg 3X day, Nystatin 500,000units oral capsules two 2X day for 6 weeks on/2 weeks off cycles. Also on tryptanol 5mg nightly, 3mg melatonin nightly, digestive enzymes 3X a day, cytobifidus bacteria 1 tsp 2X day, vitamin B, C and zinc one daily. Chromium 200µg one daily, Selenium 50µg daily, Efamol marine 2X day, Vitamin E 500mg 1X day, Co enzyme Q10 10mg 1X day. He is currently improving with no headaches, normal sleep, less muscular pain, less fatigue and occasional GIT symptoms.
Medical Diagnosis, Suicide and CFS
Upon which side of the desk lies the neurosis?
by Dr Michael King, PhD, MSc, M.A.P.S
172 Albert St,
In a very humorous talk about a very serious topic psychologist Michael King illustrated that the basic lack of recognition of CFS is causing it to go undetected in youth suicide figures and as a suicide risk factor.
What he and a lot of others do know is that CFS, "whatever you want to call it ", IS leading to suicide, but nobody acknowledges it .CFS induced suicides are being explained away in psycho babble "maybes" . As an example he read from the case notes of a case of a 26 year old, undiagnosed CFS male, who had committed suicide in 1997 . It was noted that he had had many absences in the last 2 years due to glandular fever, the conclusions of the report were however - "Maybe early signs of depression had been missed", "Maybe something had happened at work... , "Maybe his broken relationship... " Maybe he had concerns over his sexual identity " Maybe his drug usage was a factor". Michael asked the audience to think "MAYBE it is not as difficult as all this, MAYBE there is a simple explanation, MAYBE the guy was actually medically ill? Why isn't the simple explanation looked for before proceeding on with formulating complicated convoluted "social" causes?
"As doctors you have to be prepared to diagnose the condition" he said, and if you diagnose it as depression and you are wrong you are doing a disservice to your patients. If you don't know the difference you are out of step with the literature. "You can use some psychological tests to help you -eg the digit span memory/ forwards and backwards. CFS patients have cognitive difficulties which are different to those seen in depression. The cognitive deficits do not change irregardless of whether or not the patient says they are having a good or a bad day. These difficulties make school work or further education difficult or impossible. It is the organisation of material in time and space that is a problem.
For the afflicted adolescent, diagnosis would be a start . He or she is forced to put life on hold for an indefinite period of time. As months , then years go by the victim of CFS will say silently " I've suffered enough.. I got sick.. I felt awful.. I waited.. They said I'd be better by now, but I'm not.. will I ever feel OK again?" They have to say it silently , because even those who care are sick of hearing it...
The future will seem bleak to these patients because it is. "Recognise this". The person is sick and currently there is little medical help and they receive little or no support from anywhere. Doesn't this warrant a place in suicide risk factors of our training schools? Apparently not - the latest one day "travelling circus" [his term] on youth suicide risks (supported by the College of GPs) spent a lot of time discussing the trivial, the self evident and the cliches . The "Watch for "signs included - heavy metal music, social isolation etc . Nothing was said of medical illness, let alone CFS.
The facts are that:
- CFS is a diagnostic disorder different from depression and which corresponds to a medically related increased suicide risk.
- If a treating doctor fails to recognise CFS, then the corresponding suicide risk corresponding to CFS can not be correctly anticipated and managed
- Too many suicide awareness programs focus on social issues rather than medical issues and therefore also do not prepare medical professionals to recognise the special suicide risks associated with CFS. 'Keep Yourself Alive', supported by the Australian College of GPs is but one example of a suicide program which ignores CFS.
Family therapy isn't going to help the ill youth although educating the parents particularly fathers would help. He concluded his talk by discussing the affliction physicians get which happens when they are unhappy about diagnosing a disorder which is not yet understood. He called it the "neurosis of omniscience". It is this neurosis about the diagnosis of CFS which needs the cure. Next time a doctor reaches the conclusion that this disorder involves the neurotic distortion of symptoms and desperately denies the facts, he hopes we as patients question : Upon which side of the consulting desk lies the neurosis?
Serum Potassium and Hormone Responses to Exercise
by Dr Richard Burnet
Royal Adelaide Hospital
Ten years ago Dr Burnet became interested in CFS after seeing a lady who he decided to try the drug Spirinolactone on. Her fatigue improved on it, off it she relapsed. Amongst other things the drug causes potassium retention.
Last year he presented a study of 23 patients . 2/3rd of the patients showed Total Body Potassium reductions - up to 10% or more, these were 'fatigue only' patients. In the other 1/3 with 'myalgia and fatigue' total body potassium levels were high. They postulated that for the 'fatigue only' subgroup potassium handling problems could be at fault. Potassium is primarily an intracellular ion with 80% being present in muscle, 10% in the brain and 10% in other tissues.
This year, in a small study of 11 CFS patients (6F, 5M) and 11 age sex matched controls they studied the effects of exercise on plasma ACTH, growth hormone, prolactin, cortisol , sodium, potassium and bicarbonate. Subjects were exercised for 10 mins on a cycle ergometer at a work load of 75% maximal oxygen consumption. Blood was taken at one minute intervals for ten mins and 5mins thereafter for 70 mins.
At rest all values were similar between the two groups, except that patients had significant increases in ACTH levels.[ACTH is the chemical mediator released from the pituitary which activates the adrenal gland to produce cortisone]
The response to exercise of growth hormone, prolactin and sodium was normal. The 3 key findings were:
- During exercise ACTH release increased cf with controls, but cortisone release increase remained at similar levels to controls. ie Excess ACTH release on exercise does not have a concomitant cortisone increase. This suggests that the there is no abnormality of the pituitary hormonal response, but a diminished adrenal -cortisone response [Ed note: Ted Dinan (Ireland) has shown that the adrenal gland is smaller in volume in CFS]. This is seen in long term chronic stress and other chronic disabling illnesses.
- Potassium release in patients was delayed and the peak level was lower. This suggests that there is an abnormality in potassium handling which could be due to the reduced total body potassium or due to some other reason for reduced potassium flux across cell membranes. [This finding dovetails nicely with the Channelopathy concept]
- Bicarbonate followed a similar curve, which equates with excess lactate production.
Q. Is there any implication for therapy?
A. For the lactic acid muscle pain patients try potassium bicarbonate 1/2-1tsp in water daily, or using Citravecence (the urinary tract infection mixture).
Biochemical Abnormalities in CFS
by Dr Clifton Bligh
Royal Northshore Hospital CFS Unit,
Department of Endocrinology,
In conjunction with CPR Unit,
Bioanylytical Research Group
Dept of Biological Sciences,
University of Newcastle,
One hundred CFS patients plus 83 age/sex matched controls had urinary amino acids and organic acids measured at the CPRU Unit at the University of Newcastle. The most striking difference between CFS patients and controls was a reduction in urine asparginine (p<0.0001) and a reduction in urinary succinic acid (p<0.0003) in patients with CFS. Both of those correlated together (p<0.00001). Fasting plasma glucose was not low enough for hypoglycemia but it did correlate with succinic acid (p<0.002)[succinic acid is the one of the end products of glycolysis] UM17 and phenalanine were also significantly reduced. Also urinary tyrosine (p<0.04) and urinary 3-methyl histidine (p<0.03) were significantly increased in CFS. Increased tyrosine was associated with fatigue, muscle pain, lymph node pain and cognitive disturbance.
The discussion then considered why the reductions in particular? Was it because of depleted body stores or was it because of some other independent reason eg that renal tubular function/ reabsorption could itself be altered in CFS?.
Other correlations showed reduced cognitive function correlated with low urinary glycine and UM14. Pain correlated with UM 15b with is thought to be a metabolite of Paracetamol.
Chronic Pain, Protein Turnover in Polysymptomatic Patients
by Dr Neil Mc Gregor
CPRU Unit University of Newcastle,
In collaboration with Royal Northshore Hospital CFS Unit
Data from 3 studies was presented. Key reminder points were made :
Patients with CFS report an infection-like event at onset and evidence of activated immune systems. Chronic muscle pain patients have increases in infectious events at or preceding onset.
Injections of cytokines result in pain and fatigue
60-70% of CFS patients also experience myofascial pain syndrome (localised head, neck , shoulder pain)
Pain is mitigated by the action of the NMDA receptor. This receptor is activated by the excitory amino acids glutamate and Aspartate. The rate of decay of the action potential is mediated by the concentration of the amino acid glycine. Catecholamines are the major inhibitory factors of the actions of the NMDA receptor.
Study 1- RNaseL, sIL-2r, IL-6 and CFS CFS literature suggests RNaseL, sIL -2r and IL 6 are elevated in CFS and serve as predictor markers of CFS. Blood of 31 CDC defined CFS patients and 31 age/sex matched controls were sent for independent assessment. Out of the 3 measures high RNaseL (measured by only by low, medium, high levels NOT titres) was the best predictor by regression analysis of fatigue severity in CFS. However it did not predict symptom variation (or pain) in CFS. In patients with just myofascial pain there was no relationship found with RNaseL.
Study 2 - Pain severity in chronic myofascial pain syndrome 29 defined myofascial pain patients and 34 age/sex matched controls filled in questionaries and their urinary profiles were conducted along with coag negative staph studies (from nose and genital areas) and regular lab tests.
The stand out features were:
- the correlation of increased pain severity with increased levels of tyrosine and reduced levels of leucine. [high tyrosine:leucine ratio] . Tyrosine is a marker breakdown of protein, leucine is a marker for protein synthesis, therefore there is an increase in breakdown yet synthesis is impaired.
- a strong relationship found between the carriage of coag neg staph and increase in myofascial pain scores.
- females had reduced plasma sodium with increased pain severity (males little difference), whilst males had increased potassium with increased pain (females wasn't as marked) ie this implies is a sex related difference in Na+/K+ ATPase activity .
Study 3 - Myofascial Pain in CFS 100 CDC defined CFS patients and 83 age/sex matched controls selected independently at the Royal Northshore CFS unit were given questionnaires and samples collected. The prevalence of Myofascial pain in the group was 69%.
- Increased urinary tyrosine:leucine ratio was found to correlate with increasing pain severity in CFS patients. It was highly associated with symptom variation - muscle pain (p<0.00001), sore throat (p<0.05) but NOT with fatigue.
- Multiple carriage of coagg negative staph was associated with increasing pain symptoms (p<0.002) [Other secondary infections could potentially also be doing this.]
- Increased Rnase L is a good predictor of CFS fatigue
- The increased urinary tyrosine: leucine ratio is found to be a good predictor of CFS pain/infectious symptoms.
- Both however act independently and do not correlate.
- Therefore the symptom variation - pain /infectious symptoms are thought maybe due to secondary problems and different mechanisms.
- The biochemistry and microbiology associated with myofascial pain was the same in both CFS patients and non CFS myofascial pain patients and appears to represent a distinct tissue specific entity.
Neil hypothesised that possibly an HIV-like model best describes the cause of the variability of symptoms seen in CFS patients. The initial onslaught (viral /chemical) damages selective membrane channels - this upsets cellular dynamics. RNaseL activity remains high, causes a resultant dysregulation in protein synthesis which leaves the body vulnerable to secondary problems/infections, which may vary in each patient. He suggests patients need to have viral studies, RNaseL testing and testing for mycoplasma, coagg neg staph, rickettsia.
Infection, Psoas Muscle Damage and Dysautonomia
by Dr Breck McKay
PO Box 353,
This presentation was an interesting new angle on CFS. The psoas muscle is a deeply set muscle in the lower back which holds and gives strength to the lower spinal column. It is a fast twitch muscle which consequently uses a lot of ATP (ie energy). It is a muscle that over our evolution to the upright stance has been overstretched and consequently is vulnerable to injury. In females the muscle changes more at puberty and he wondered whether this may explain the 3:1 female:male ratio we see in patients with CFS.
In CFS patients in the upright standing position (this is important as lying down the X ray looks different) he showed by cross sectional CT scans that the psoas muscle was damaged and even atrophied in many instances. This then put the spine out of alignment and could possibly account for some of the symptoms of dyautonomia reported in CFS and FM. He postulated that if the cells of this muscle were infected with something which deprived them of ATP eg mycoplasma, rickettsias, chlamydia, then the damage would show like this on imaging . Treatment with antibiotics and "Front to Back" physiotherapy protocol (to restrengthen the muscle involved) had shown some rapid recoveries. The physiotherapy protocol is explained in the book called "Front to Back", Jefferis (1996) Adelaide. ISBN 0 646 24827 8.
Hypercitricemia in CFS by Alex Young (Queensland)
Citric acid levels in the urine of CFS patients are high and is just thought to be a result of a dysfunctional Krebs Cycle. Alex argued the case that possibly this hypercitricemia is initiating a cascade of abnormally elevated or suppressed biochemical pathways and feedback effects that result in chronic tissue hypoxia. The theory predicts disruption to cell membranes, upregulation of nitric oxide, and depletion of many aminoacids.Thoughts on therapy ongoing.
Epidemiology by Dr De Meirlier (Belgium)
From data on 1210 patients presenting at an outpatient clinic with symptoms of prolonged fatigue, 752 fulfilled the CDC CFS criteria. Oxygen Uptake as a measure for disability was looked at by Dr de Meirlier. He found that maximal oxygen uptake was impaired in CFS and could possibly be used to determine the degree of disability.
Women fitted the AMA Rating of class 3 impairment, Men class 2. Controls had no impairment. Usefulness of a readaption program was looked at by Dr de Meirlier. In a 20 patient , 12 month study, where 13 patients dropped out, he found that whilst low level exercise programs can be advantageous, they have to be individually adapted and can not be compared to reconditioning programs for healthy people. Normal levels were never reached but for those patients who could adopt the program they did feel an improvement in wellbeing but the illness did not go away.
Blood Transfusions were investigated by Dr de Meirlier. Of 752 patients, 34 had received a blood transfusion within a week of developing CFS. In 9/34 patients the LMW RNaseL test was performed and all 9 were found positive. Because these findings point towards a transmissable cause he advised that patients should not be blood donors.
Secondly he advised the administration of blood transfusions has to be very carefully considered and given when strictly necessary and not as standard procedure eg after the delivery of a baby.
The Rickettsial-like organism - Coxiella burnetii (the cause of Q fever) and its relationship to CFS was investigated by Bernhard Liedtke and Bill Paspaliaris (Melbourne).
Using a new test for detecting anti- C. burnetti antibodies in sera, they are finding that positive results in 50% of patients. (Control average 8%). This suggests that the circulating antibodies to the causative agent of Q fever are higher in CFS patients than the general population. The contribution the infection is making to symptoms in CFS is unknown, yet the symptoms of Q fever are very similar to Me/CFS. Treatment would be with antibiotics like for Rickettsia.
Is CFS/FM due to a hypercoagulable state?(Berg, HEMEX Laboratories, USA)
9 CFS patients and 12 FM patients, were tested using new sensitive assays for evidence of a hypercoagulable state using 4 tests - Fibrogen (F1+2), Soluable Fibrin Monomer, Sonoclot score and platelet activating score.Results showed a hypercoagulable state by demonstrating thrombin (IIa) generation in these patients. Soluable Fibrin monomer deposition acts like a Teflon coating on endothelial cells lining the capillaries and blocking passage of nutrients to the muscles , organs etc. Shutting off thrombin generation should allow the fibrin deposists to dissolve. To downregulate thrombin generation (immune activation) anticoagulant therapy was tried with low dose heparin followed with low dose coumadin. 20/21 Patients showed moderate to significant improvement. Low dose coumadin is able to prevent symptoms returning. A long term placebo controlled trial is underway. http://www.hemex.com/csf_fmabstract.htm
Q. OK so we are hearing antiviral and antibacterial approaches being taken. What does one do first?
A. Dr Kenny de Meirlier - If it is indicated treat viral first with Ampligen, only medication going through FDA process for CFS. (sees everything else as secondary in those with 37Kda)
A. Prof Garth Nicholson - If mycoplasma positive, treat . Believes chronic infections can cause an increase in cytokine activity.
A. Dr John Martin - If evidence of viral activity, treat anti-virally, 2-3 weeks Gancyclovir.
Q. As a GP , what are the best tests to try to narrow down a viral CFS? We don't have access to many of the tests you are talking about.
A. Dr Kenny de Meirlier. The minimal battery would be to look at : 1)general RNaseL activity (this would be high) 2)CD4/CD8 ratio (this will be high in the very ill and very symptomatic) 3) NK number and function (numbers high, function low)
Q. Should an CFS patient donate blood?
A. Dr Neil McGregor . A poster by Kenny de Meirlier showed that one of the risk factors for getting CFS was a recent blood transfusion, so from this I'd say no.
A. Dr Abhijit Chaudhuri. In the UK people aren't allowed to be donors unless in good health for last 6 months, this therefore excludes people with CFS by definition.
A. Prof Garth Nicholson. The screening of blood for a lot of infections including mycoplasma is not good, so therefore, no, do not give blood. Witness the Hepatitis C problem. Caution is best.
Q. I'm finding low DHEA and testosterone levels are others?
A. Dr Kenny de Meirlier sees low normal levels, thinks its a secondary phenomena.
A. Prof Garth Nicholson finds they normalise after effective therapy.
Q. Does anyone use IM magnesium sulphate?
A. Dr Richard Burnet said IM was controversial and didn't do it, also very painful.
A. Dr Schloeffel saturates with magnesium orally, or when doing a slow IV Vit C drip he adds magnesium. FM pain seems to be helped.
A. Dr Neil Mc Gregor - it works at the NMDA receptor so it theoretically should help pain.
Chris Hunter made a citation to US author Hillary Johnson, for her outstanding work in documenting the history of CFS in her book 'Osler's Web'. She also made a plea for the physicians present to share their approaches and recommendations. She particularly noted that in Adelaide access was available for hospitalisation and central venous lines, plus IV nutrition and hydration. It can happen and doctors must work together to make it happen for their sickest patients nationwide.
Experience from Clinicians
1. Work ups
Drs Richard Stovell and Mark Donahue Both emphasised the need to take a full history, to have a systems review in place and to set a program of investigation and management. They both observed the CDC criteria, but found that clinical signs were observed and included : -the 'brain fog', -sinus tachycardia, hypotension, postural hypotension -heavily coated tongue -cervical, axiilar and inguinal tender lymphadenopathy -cold hands and feet -neurological signs, especially onesided eyelid droop (ptosis) and dilated pupils -abdominal tenderness, distension -gross weight loss or obesity Of the exclusionary testing advised by the CDC, the thyroid in particular warranted constant attention.
Dependent on clinical history they also investigate:- Antinuclear antibody--Anti-gliaden antibody-Anti-endomysial antibody-Reticulum antibody-EBV, CMV, Toxoplasmosis tires, especially in patients with ongoing lymphadenopathy-Lyme disease titres -Burmah forest virus titres-Ross river virus titres-HIV, Hepatitis B and C studies -PCR for mycoplasma-Rickettsia DNA screen in blood (Micro Aggulation test not available)- Giardia Lambia DNA from faeces ( may be useful, not reliable though)
Other tests ordered dependent on symptoms: -24 hour Holter monitoring -Tilt table testing -Newcastle Uni testing of urine,blood,faeces, coag neg staph - Nuclear medicine gastric emptying time studies and bowel transit time in severe GIT dysfunction with hyperemesis and weight loss -Key symptoms that can be managed currently are *Sleep - 10-20mg Amitrip, or 25-75mg Prothiaden nightly for pain, stage 4 sleep *Activity - important to explain consequences of both under and over exercising
Hypotension - as Dr Peter Rowe, Johns Hopkins protocol
Secondary infections -mycoplasma, rickettsia - as suggested with careful attention to yeast overgrowth and nutritional support
Subclinical hypothyroidism -thyroxine 50-100 ug/day
Viral activation/reactivation - new antivirals when available eg.Gancyclovir. - Hugh Dunstan (Biochemist, Newcastle) explained the tests now available from Newcastle and their common findings. He emphasised that their work should be viewed as "work in progress".
The Metabolic Profile - Urinary amino and organic acids. They have been able to analyse CFS patients into 6 subgroups. Dependent on the deficiencies of a particular patient and some other key markers, specific amino acid replacements are now being able to be formulated. Whether they are being helpful he wants to know from clinicians/patients.
Faecal Analysis - Common findings are that the gut flora distribution is disturbed. The aerobic (bugs that use oxygen) counts are commonly higher than normal. Within the aerobes, E.Coli is reduced <50%, whilst other aerobes eg Enterococcucus are increased. Whilst the anaerobic (bugs that don't use oxygen) count is normal, the distribution is abnormal with Bacteroides increased >95%, and Bifidobacterium nad Lactobacillus and Clostridia all decreased. Also Faecal lipids show cholesterol % to be reduced, in 2/3rd of patients. The pathway to cholesterol uses CoQ10 - what's happening here he asked? Also Mycoplasma require sterols to survive does this have any bearing?
Blood Lipids - this assesses the Essential Fatty Acid metabolism, some problems are indicative of infection.
Staphylococcal toxin testing (swabbed from nose, genitals) 13 species of coag neg staph have been identified and in the past have been reported as harmless commensal bacteria. They don't think this is the case. In CFS patients they are finding multiple carriage, also in those reporting pain. Other organisms may well be producing toxins eg Mycoplasma, rickettsia. It is the toxins that they think cause the pain.
2. Clinician Reports
Robert Hannah (Melbourne) reported that whilst he has used antibiotics on some Rheumatoid patients for 8 yrs, he worries about it for CFS patients. He has been selective in who he has used antibiotics on and but has had some good outcomes. He uses Zithromax/Doxycycline in an amended version of Nicholson/Jadin approach. With respect to amino acid supplementation ex Newcastle Urine reports, 9/19 patients have had significant improvement, some got worse, some didn't respond.
Richard Schloeffel (Sydney) found 60% of his patients mycoplasma positive, 10-20% both mycoplasma and rickettsia. He prepares the patient beforehand with diet, supplements, low stress etc, works heavily on preparing the gut. Then uses 7 days on 21 days off approach of Jadin. Combination Doxcycline 100-300mg plus Cipro 150-200mg. About half of his patients are doing well, he finds it encouraging but worries about longterm effects.
Don Lewis (Forest Hill ,Victoria) discussed the care needed with patients - the humane care. He asks the patients to write their own history, with some guiding questions given by him. He receives this and reads it before they meet. The first appointment he makes for a suitable time for the patient - when they are at their best, usually a 2pm . He provides them with information as he knows they can't remember things. Often finds it useful to have a significant 'other' accompany the patient so they remember things. He treats one symptom at a time. Careful review paramount. Has found treating NMH helpful . He uses the 15min stand test (ex Dr Peter Rowe). Out of 71 patients 78% were positive. By using increased water and salt, 45% improved, in those that didn't he added Florinef and then Beta Blockers as suggested by the Johns Hopkins protocols.He also discussed his gratitude for the Newcastle tests . He thought they were very useful but he reported however that patients are 1)confused about what the results are telling them, 2) don't know what to do about the results 3) Many are hesitant to buy amino acids in bulk because some have become unwell , so he suggested test samples of amino acids should be made possible.
Mark Donahue (Sydney) discussed the need to exclude iatrogenic problems. For example remember that H2 antagonists reduce the liver detoxification pathway, diuretics deplete needed magnesium and aggravate hypotension.
Ian Stewart (Sydney) discussed a patient with a 14 year history of CFS, on which he got a positive Rickettsia test. He wondered how she could be positive assuming it a European illness with rash etc. The patient then recalled that she had had a similar illness to what he described at a campground their family went to every year, where their were lots of European campers. He treated her and within 3 weeks she was marvellously better. With other patients he has not found the same startling results. Needs Jadins testing methods.
John Whiting (Brisbane) discussed the nasal swab testing for Coaag neg Staph ex NewCastle. He found this often was positive when a patients complaints were primarily sore throat, post nasal drip, gastritis, hayfever. He treats with nasal Bactroban and is finding 80-90% improvement in symptoms. He firstly treated for a week, but found patients were relapsing after stopping so now is using it for much longer periods and is also trying other antibiotics. He noted in this group of patients that their noses were extremely tender to swab. He also found a large number of patients with high H. pylori on breath test.
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