Dr Rosamund Vallings
Program and Abstracts
On Friday 26th February, 1999, I attended a clinical and scientific meeting for medical practitioners and scientists put on in Sydney by the Alison Hunter Memorial Foundation. The theme was "The Challenge of Chronic Illness", and was particularly focused on research into diagnosis and management of Chronic Fatigue Syndrome and its subcategories. The meeting was coordinated by the research team from Newcastle, NSW, headed by Professor Tim Roberts. The conference was well attended by participants from around the world.
Simon Molesworth, QC, whose son suffers from CFS, opened the conference. He gave an emotive and heartwarming address particularly addressing the need to recognition and support for sufferers and their families. He had been well presented on TV news the previous evening, which has no doubt increased awareness. Later he stressed the importance that as medical practitioners we need to be diligent in making a correct diagnosis and managing this illness to the best of our knowledge in light of current research. Litigation for misdiagnosis is a reality. We are vulnerable if we dismiss CFS as somatisation disorder or another manifestation of psychopathology.
Neurological mechanism of CFS
The first scientific paper was from Abhijit Chaudhuri, who is a neurologist and part of the team working with CFS in Glasgow, Scotland. He initially reminded us of the CDC criteria for making a diagnosis. He focused on some other symptoms which do commonly occur such as alcohol intolerance, concentration difficulties, migraine-type headaches, irritable bowel, chocolate craving (40%), paroxysmal sweating and chest pain, tremors, myoclonus and hemisensory symptoms, lightheadedness and fainting, failure to accelerate heart rate efficiently and a tendency to atopy. He then outlined some of the abnormalities frequently found on investigation: leucopenia, low steroid metabolism, serotonin and cholinergic supersensitivity, abnormal cerebral and cardiac SPECT scans, reduced exercise capacity, impaired aerobic metabolism of skeletal muscle, low carnitine levels, raised prolactin.
As a neurologist, he finds that fatigue is similar to that which occurs in many neurological disorders. The mechanisms may be anatomical (e.g. a "fatigue generator"), functional (neurochemical or hormonal), a cellular metabolic defect (e.g. mitochondrial disease), cytokine effects or hypothalamic disorders. He feels it is likely that in CFS there is channelopathy. He used ciguatera poisoning as an example of a channelopathy. The toxins attack the sodium ion channel allowing potassium to escape from the cells. Viruses also attack the sodium and the calcium channels. The ion channel changes can explain the neurochemical sensitivity and provides a rational basis to explain the fluctuating fatigue and related symptoms in CFS. 30% of our energy is used to maintain the ion mechanism. The resting energy expenditure in CFS is very high as the individual tries to correct the abnormal ion channel function, so that when the person with CFS exercises and takes up energy, there is not enough to maintain the mechanism, and symptoms are induced.
Multisystem Stealth Viruses and Encephalopathy
W. John Martin, now working at the City of Angels Medical Centre dedicated to the study of stealth viruses, described this group of viruses as foamy, vacuolating and cytopathic with absence of antiviral immunity. They have the effect of causing systemic infection with a spectrum of neuropsychiatric manifestations, such as autism, ADD and behavioural disorders in children and chronic fatigue, depression, Fibromyalgia and severe motor, sensory and cognitive diseases in adults. They can induce severe illness in cats. These viruses have oncogenic potential.
Genetic sequencing studies show that portions of the virus are related to human cytomegalovirus, but it is unrelated to known CMV sequences. It is more closely related to CMV from African green monkeys. CMV is a member of the herpes family and only causes illness if the immune system is not working properly. Widespread illnesses involving multiple family members and whole communities can be attributed to the spread of stealth virus infections.
He went on to describe the Mohave Valley epidemic characterised by a gastrointestinal illness in 1996. 10% of the population were affected and many had neurological signs. Many continued with a chronic relapsing illness, and a likely diagnosis is a stealth virus encephalopathy. 18 of 19 patients tested positive for a stealth virus.
A case study was presented of a young boy with a grossly abnormal MRI, who was finally successfully treated with gancyclovir.
Mycoplasma in GWI, CFS, FM, and RA patients
Garth Nicholson from California describes this group of diseases as having many overlapping signs and symptoms and his team have found that chronic viral and bacterial infections and likely to be implicated. He explained that infections in illness can be causative, cofactor of opportunistic. Many diseases are implicated. He theorised that multiple exposure over time to chemical and biological stressors coupled with genetic predisposition can lead to illness. The organisms implicated in his studies are mycoplasma, chlamydia, brucella, borellia, rickettsia.
He then presented studies of Gulf War Illness (GWI), of which there were 200,000 sufferers in the USA. The illness is similar to CFS and other family members have succumbed, suggesting an infectious illness. There are multiple apparent causes. Routine investigations revealed abnormalities in the CD4/CD8 ratio, abnormal NK cell count, changes in the ANA with progression of the disease, occasional abnormal brain SPECT scan. The abnormalities in the immune system suggest underlying chronic infection. PCR testing of 200 patients revealed evidence of mycoplasmal infections inside the leucocytes, but not in the plasma or urine in approximately 50%. (cf 6% in normal healthy people). M. fermentans was the most common species. The many symptoms are thought to be due to the penetration of the bug into the cells.
Mycoplasma is a slow growing bug, which can become intracellular when the natural defence mechanisms are not working. It has an inherent insensitivity to drugs. It is often misunderstood and inappropriately treated. Mycoplasma positive cases of GWI have been successfully treated with multiple 6-week cycles of antibiotics, such as doxycycline (200-300mg daily) plus nutritional support with vitamin and mineral supplements.
CFS, FM and RA patients were then compared to those studies with GWI. 60% of those with CFS and FM tested positive for mycoplasma, as did 45% of those with RA. He concluded therefore that treatment of these patients similarly to those with GWI can be successful.
Cecile Jadin from Johannesburg, South Africa, has studied rickettsial infections extensively following the lead given by the Pasteur Institute. She has now seen many patients with chronic illnesses which have a commonality of symptomatology such as fatigue, myalgia, arthralgia, headaches, cognitive problems, recurrent sore throat, sweating, bruising, psychological and neurological disorders and balance problems. Sore throat, enlarged glands, heart abnormalities and RIF tenderness are commonly found on examination.
Diagnosis of chronic rickettsial infection is by the Giroud micro- test. Rickettsia are transmitted by arthropods and are resistant to humidity and dryness. They can survive a long time (e.g. 4 months in sand).
In the past 8 years she has seen 3800 patients who have been treated successfully with a 7 days/month regime of high dose tetracyclines plus adjuvants (such as B vitamins and acidophillus) and exercise. Alternating or combining with other antibiotics may be favourable. Treatment lasts from 6 months to 3 years and no toxicity has been reported. After the first 3 months, treatment is generally well tolerated. Cortisone should be avoided as this may reactivate the rickettsia. In those who progress slowly other factors may be involved. Reinfection and Reactivation can occur.
Rickettsia, chlamydia in psychopathologies and CFS
Phillipe Bottero from Paris confirmed that rickettsial illnesses are vascular diseases involving the reticuloendothelial system, blood vessel walls and production of vasoconstrictive toxins. He has had positive sera results for rickettsia and chlamydia infections in all patients he has seen with chronic illness in the past 18 years.
He studied 98 patients with CFS and 79 with psychological diseases treating them all with 6 months antibiotic regimes. Up to 85% patients in both groups have had positive outcomes. The studies were not placebo controlled or blinded. He acknowledges that other infections such as mycoplasma and viruses may also be implicated.
Mycoplasma: cause, co-factor, or commensal in CFS
Bill Paspaliaris from Melbourne presented further studies on mycoplasma. He described them as the smallest free-living organisms known, distinguished by the absence of a rigid cell wall. M. fermentans is reported in high incidence in chronic diseases involving abnormal states of the immune system. Pathologic potential is still undecided, and it may be a co-factor.
His research has been to determine the presence of mycoplasma in CFS. It was detected in controls (14%), but the incidence was significantly raised in CFS patients (45%). The DNA load was also significantly higher in individuals than in asymptomatic M. fermentans-positive controls. M. fermentans monocyte/macrophage activator protein expression was performed from RNA isolated from buffy coat layers of peripheral blood and a striking pattern of differentiation was observed in CFS patients compared to asymptomatic individuals.
He believes that the expression of M.fermentans monocyte/macrophage activator proteins may be a most useful clinical marker for detecting its pathogenicity in chronic illnesses such as CFS.
CFS and Infectious Diseases
Other infective conditions have to be excluded before a diagnosis of CFS can be made, and Bernie Hudson from RNS Hospital in Sydney addresses the issue of Lyme disease. he explained the difficulties experience with testing for many potential infecting agents causing an illness fitting the CDC criteria for CFS.
Lyme disease is caused by a spirochete leading to erythema migrans. It should be one of the infectious diseases to exclude before making a diagnosis of CFS. The organism Borellia burgdorfei or gerinii comes from a tick, now thought to be common on the Eastern seaboard of Australia. The bite gives a local reaction, and may be followed by a generalised allergic reaction. Tick bite paralysis, spotted fever and Lyme disease may ensue. It is a generalised disease with considerable overlap of symptoms with other spirochetal disease. Spirochetes have been isolated from NSW ticks. 9 cases of Lyme disease have occurred in NSW. Diagnosis must be confirmed by a 4mm punch skin biopsy, as blood tests may be negative. The initial lesion is characterised by a spreading rash around an initial bite. 1% patients will develop major CNS problems and 1% experience arthritis. There is often a massive Herxheimer reaction with antibiotic therapy. Treatment is with either doxycycline 200-300mg daily for 14 days or amoxil can be used. More than one type of spirochete may be involved and some cannot be cultured. They can persist for 10 years and every antibiotic tried does have a failure rate.
RNase-L dysfunction disorder in CFS
Kenny de Meirleir from Brussels began by expressing the difficulties experienced in making a diagnosis of CFS with its unknown aetiology and absence of a diagnostic marker. Activation of immune responses and infection by viruses have been suggested in several studies. Following on from Suhadolnik's work on Rnase-L activity in CFS, de Meirleir presented his work exploring the specificity and sensitivity of the presence of the low molecular weight (LMW) Rnase-L in CFS.
Rnase-L is an interferon-induced enzyme, activated by 5'phosphorylated,2-5 linked oligoadenolates (2-5a). 18 controls and 57 patients were studied. The patients all had acute onset leading into a post-viral illness. Duration of illness was 6 - 8 years. He used a different technique to Suhadolnik. He found that the LMW 2-5a binding polypeptide distinguishes CFS patients from controls, being present in 95%. This is associated with increased activity of the enzyme.
He also noted that the CD4/CD8 ration was elevated and the NK cell count was decreased in patients, and this response does not occur in mycoplasma or rickettsial infections.
Medical diagnosis, suicide and CFS
M.G. King, a psychologist from Victoria feels very strongly that we must include a diagnosis of CFS as a significant risk factor for suicide. He stated that there is a lot of neurosis associated with this illness, but is the neurosis associated with the patient or the doctor?! If the treating doctor does not diagnose CFS, then that suicide risk corresponding to CFS cannot be anticipated and managed. CFS continues to manifest as a disorder, which is diagnostically different from depression and corresponds to a special class of suicide risk. All too often suicide awareness programs for health professionals focus on social rather than medical issues such as CFS.
Serum Potassium and Hormone Responses to Exercise
In earlier studies by Richard Burnet and his team from Adelaide, mean serum total body potassium levels were found to be significantly less than in controls. The patients will feel more ill the lower the potassium.
Using exercise tests the potassium levels rise slower on exercise in CFS than in controls, and the potassium is lower than in controls during recovery. He concludes that there is an abnormality in handling of potassium with an abnormal and reduced flux of potassium across the cell membrane and exercise or a decrease in total body potassium. This fits in with a possible channelopathy. Bicarbonate was also measured in response to exercise and was lower than in controls and this equates with excess lactate.
The ACTH/cortisol response to exercise was also studied. There was no abnormality of the pituitary hormone response to exercise in those with CFS, but a diminished adrenal response to ACTH as seen in persons with any chronic debilitating illness. There was no significant difference in growth hormone or prolactin after exercise.
There has been no demonstrable abnormalities in either DHEA or androgen levels.
Biochemical abnormalities in CFS
Following on from the work by the Newcastle team on urinary amino acids and organic acids, Phillip Clifton-Bligh and his team at Sydney's RNS Hospital studied the overnight excretion rates of a number of amino and organic acids in 100 CFS patients and 83 controls. The most striking differences between patients and controls was a reduction in urinary asparagine and succinic acid. Tyrosine (a protein catabolism marker) and 3-methyl histidine were significantly increased in CFS patients. Tyrosine levels correlated with fatigue, muscle pain, lymph node pain and cognitive disturbance.
The reasons for these abnormalities were addresses. Low asparagine may be due to low serum levels, excess tubular resorption of asparagine or depleted stores. Low succinate may occur because succinic acid synthesis may be reduced, serum succinic acid may be reduced, there may be increased tubular resorption or there may be reduced availability in the cells of the precursor succinyl co-enzyme. The low succinate levels correlated with low fasting plasma glucose.
Raw depression scores did not correlate with any urinary peaks, but cognitive function scores correlated with glycine and UM14 scores. Pain was found to be associated with UM15b, which is a metabolite of Paracetamol.
Chronic pain, Protein Turnover in Polysymptomatic Patients
Chronic pain is a major reason for seeking medical treatment and the mechanisms are still poorly understood. Neil McGregor, from the Collaborative Pain Research Unit in Newcastle, NSW, has studied the metabolic events associated with chronic pain. He noted that an injection of cytokines, is associated with pain and in CFS and its associated disorders, an activated immune system is likely. Certain patterns of symptoms go in clusters and different patterns are associated with different biochemistry.
He has looked at myofascial pain syndrome (head, neck, shoulder, trapezii involved). There is an increase in total amino acid output. ALT, AST and urea are elevated (markers of tissue damage). Sodium serum is reduced in relation to pain severity (in females), and in males the overall potassium is higher in those reporting muscle pain. The metabolic events associated with chronic pain are distinct from those associated with chronic fatigue.
Leucine levels correlate normally with protein synthesis and tend to be decreased in CFS. The tyrosine/leucine ratio is associated with symptom variation and is strongly associated with chronic muscle pain, but is not related to fatigue.
He explained a mechanism whereby tricyclics maybe useful in the management of chronic pain. He finished by saying that understanding the mechanism of chronic pain is essential for the development of appropriate therapies.
Infection, Psoas Muscle Damage and Dysautonomia
A. Breck McKay explain the condition known as Adelaide Brisbane Serendipity (ABS) Syndrome, which is the relationship between the effects of mycoplasma, rickettsias and chlamydias on the cellular energy supply of the muscle, mucosal and other cells (a channelopathy); the evolutionary change to human fast twitch psoas muscles, resulting in overstretching and susceptibility to injury; the secondary effect of muscle damage and spinal alignment, causing dysautonomia characteristic of CFS, FM, etc; and the use of a physiotherapy protocol coupled with appropriate antibiotic treatment. He reported some very favourable responses to this approach.
Abhijit Chaudhuri (Glasgow) and Garth Nicholson (California) were both called upon to outline their approaches to therapy.
Chadhuri initially stressed that the basic mechanism in CFS lies at the level of the ion channel. This is shown in muscle biopsy, in which a number of abnormalities are found. There are abnormal mitochondria, reduced intracellular potassium, reduced creatine and glycogen, abnormal pyruvate/lactate levels, normal ATP and ATP/ADP ratio, normal concentration at the sodium-potassium pump and no evidence of disuse or atrophy.
He uses a variety of treatment options some in combination. Low dose tricyclic antidepressants are high on the list to alleviate sleep disorder and chronic pain. Cognitive behavioural therapy and physical exercise are important considerations. Steroids (gluco- and mineralo-corticoids) are worthwhile in some patients. Immune modulators, such as Ampligen are inevitably useful, but not readily available yet. Anti-epileptics such as carbamazepine and lamotrigine are membrane stabilisers, the latter being a sodium channel blocker and are often appropriate, as are ion channel blockers. Anticholinesterases, dopamine agonists such as amantadine and bromocriptine, stimulants and MAO inhibitors all have potential. He feels that antibiotics are not necessarily suitable treatment and benefits felt by patients may be from side effects, such as the anti-inflammatory effect. He stressed that our aim should be to treat symptomatically initially with ongoing regular review of symptoms and diagnosis.
Nicolson's main thrust of treatment is towards elimination of the mycoplasma. A positive diagnosis for chronic infections must be made first however. Antibiotics (doxycycline, azithromycin, ciprofloxacin or clarithromycin) are to be used, but there are certain recommendations to be followed. Doses must be high and duration of therapy should be for 6 months with 6 week cycles to follow. Herxheimer reactions are likely, but may be less with IV therapy. Combination with antivirals may be appropriate. Switching or pulsing antibiotics may be necessary to avoid side effects. Patients must be warned to avoid sun exposure if on tetracyclines and the dose should not be taken at the same time as supplements.
While patients are on the antibiotics, he uses immune modulators, nutritional support, acidophillus and he encourages moderate exercise and saunas. He recommends saunas as they are thought to leach out offending chemicals. He also recommends the use of hyperbaric oxygen therapy, as he has found people do relapse after long air flights and has found that mycoplasma "like" low blood oxygen.
These comments are gathered from question and discussion time and were not part of the formal presentations.
M. Donohue (Sydney): CFS is a complex of adaptive and maladaptive host responses to insults such as diet, stress, environment, infection etc. The host response affects all organ systems, and in his patient population a large number have been on long-term antibiotics. He feels strongly that we should look at predisposing factors such as stress before treating pathology.
R. Schloeffel (Gordon, NSW) who had presented 2 interesting case histories has produced a useful set of guidelines for diagnosis and management of CFS. He has found that 10% of patients end up with an alternative diagnosis.
Don Lewis (Forest Hill, Vic) sends a questionnaire to patients before their appointment to cut down on time with history taking. He also gives patients a journal for them to record progress, and for him to write instructions. He is hoping to produce a follow-up questionnaire.
Hugh Dunstan (Newcastle) working with metabolic profiles, has found these can lead towards some treatment. Plasma levels do correlate with urine levels. Patients can be subgrouped and types of amino acid requirements can be formulated. He also discussed a variety of toxins from staphylococci. 13 species of coagulase negative staphs were identified in patients, from nasal and genital swabs. There is evidence of multiple carriage of staph toxins, and there may be other organisms such as mycoplasma. Multiple carriage means a worsening of symptoms such as pain. 2/ patients do have low cholesterol and this may result from mycoplasma using up sterols.
John Whiting (Brisbane) has used intranasal bactroban for those with positive coagulase negative nasal swabs. He has had a 95% positive response. Symptoms do relapse if the course treatment is inadequate.
Ampligen studies were discussed by K De Meirleir (Brussels). A study on 44 patients with very low Karnofsky scores had been undertaken. These were very ill patients who had been ill for an average of 8 years. Treatment by IV infusion was given over 24 weeks. All symptom scores improved except excessive sleep, exercise capacity improved and Karnofsky scores went up.
A Chaudhuri (Glasgow) remarked that for those with chocolate craving, an SSRI, such as sertraline may be useful, otherwise low dose tricyclics are an important consideration.
A number of posters outlined in more detail the aforementioned formal presentations. There were also several other interesting poster presentations:
Hypercritemia in CFS (Alex Young, Queensland) - looked at the biochemical consequences of elevated citric acid levels and possible corrective strategies.
CFS in Belgium (De Meirleir et al) - 752 of 1210 patients presenting at the OP clinic with a possible diagnosis of CFS actually fulfilled the CDC criteria for CFS.
Physical disability in CFS (De Meirleir et al) - concluded that both males and females were limited in their ability to exercise/ Further studies will be done to determine severity of disability. In another poster, low level exercise training was found to be advantageous for FM patients. Ongoing monitoring is important to prevent dropout from the programme.
Blood transfusion and CFS (De Meirleir) - 4.5% patients in a study of 752 fulfilling criteria for CFS had received a blood transfusion within a week of developing CFS. In view of possible transmission of infection, patients are recommended not to be blood donors.
Prevalence of Coxiella burnetii (causative agent of Q fever) in CFS (B. Liedtke, Melbourne) - Positive results found in 50% CFS patients studied, while previous studies have found an 8% incidence in controls.
Is CFS/FM due to a hypercoagulable state (D. Berg, Phoenix) - It was hypothesised that these patients may have a hypercoagulable state and this was proven by demonstrating thrombin (2a)generation and platelet activation. Activated platelets can induce an inflammatory response in the patient. Heparin downregulates the hypercoagulable state followed by low dose coumadin to prevent relapse. Symptom improvement was noted, but this may only represent a small group of CFS patients.
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