July 10, 2008 • 9:44 am Comments Off
Hosted and organised by ME Research UK, and co-sponsored by the Irish ME Trust, the New Horizons 2008: International Conference on ME/CFS Biomedical Research took place on 6th May 2008 at the Wellcome Trust Conference Centre on the Genome Campus at Hinxton near Cambridge, UK, an outstanding custom-designed venue designed to attract the worlds leading scientists to debate issues at the forefront of new scientific discovery.
Filed under: Conference Reports & etc.
July 9, 2008 • 3:16 pm Comments Off
On 6/5/08 I attended the International conference on ME/CFS Biomedical Research at Hinxton, Cambridge, UK. 130 people attended and cutting edge research was presented from around the globe. The conference was sponsored jointly by ME Research UK and the Irish ME Trust. Sadly, Vance Spence, who had organised the conference and was going to give an introductory overview, was too ill to attend.
The conference was formally opened by one of the Patrons, Roger Jefcoate, CBE, and he described ME Research UK as a world leader in Biomedical Research in ME/CFS, which presented a signal of hope for sufferers and those taking care of them.
The first presentation was given by Prof Nancy Klimas (Florida, USA) with an overview on behalf of Vance Spence, followed by her own presentation reviewing the clinical aspects of ME/CFS. She explained how we needed to get away from clinical case definitions towards biomedical subgrouping. She described the Canadian definition as more clinical by including autonomic, neuroendocrine and immune dysfunction. She feels the most important symptom of all is post-exertional relapse. She stressed the importance now of having a paediatric case definition. Children can have a diagnosis made after 3 months of illness. Various other symptoms are included, such as rhythm disturbances of sleep as well as non restoration, more widespread and migratory pain, and the inclusion of 2 or more neurocognitive manifestations, and inclusion of symptoms of an autonomic, neuroendocrine or immunological nature.
A number of overlapping conditions such as Fibromyalgia, Gulf War Syndrome and Multiple Chemical Sensitivity were also mentioned..
Epidemiologically, this illness in the USA has an incidence of 522 per 100,000 females and 291 per 100,000 males. This leads to a 50% reduction in household income, and a 9$ billion US loss in productivity. There are probably 1,000,000 sufferers in the USA of an illness which can be as severe as congestive heart failure. In the UK, 44% of physicians lack confidence in making the diagnosis and those that do make the diagnosis more readily usually have had a family member with the illness.
The pathogenesis involves a combination of genetic susceptibility coupled with a trigger event and/or infection, whence mediators (immune, endocrine, neuroendocrine, psychological) lead to a health outcome and persistence. A slide then showed the interaction between the various body systems implicated, to explain the many and varied symptoms. The length of the illness tends to lead to an overlap and change in symptoms over time, one area affecting another.
In this illness there is an immune cascade leading to chronic immune activation, with a shift from Th1 to Th2 dominance. The immune activation leads to functional defects. The level of severity depends on the pro-inflammatory cytokines.
Viral persistence and reactivation was discussed with references to studies on HHV6, Enterovirus and EBV. In HHV6 studies, 79% of patients were found to have HHV6 activity (compared to 22-54% of controls) and 28 out of 144 were found to have HHV6 in the spinal fluid, and 7 out of 35 in another group. Clearing the spinal fluid led to great improvement in 5 out of 8 people, but the antiviral agents used are potent and toxic. Enterovirus was found in 13% of muscle biopsies and in 60% of gastric biopsies in those with gastric symptoms. In EBV the dUTPase is seen as an immune modulator up-regulating the cytokines.
Endocrinologically, there is reduced cortisol output due to various mechanisms, such as heightened negative feedback, heightened receptor function and impaired ACTH and cortisol responses to challenge. There is a possibility of DHEA abnormality.
There are many symptoms of autonomic dysfunction. These occur as a result of parasympathetic dysfunction with sympathetic overactivation. Neurally mediated hypotension, orthostatic hypotension, slow gastric emptying, heart rate variability, haemodynamic instability (shown on tilt table), decline in cognitive function after treadmill, abnormal perfusion in cerebellum, reduced perfusion in mid cerebral region, and a drop in BP causing relapse are among the many effects.
In the central nervous system, tryptophan abnormalities in the cerebrospinal fluid result from abnormalities in levels of serotonin and its precursors. PET scans have shown that 5HTP binding is reduced. There is pronounced reduction of serotonic transporters in the anterior cingulate. Reduction of grey matter in the more severely affected is evident. There is utilization of more extensive regions of the brain to process tasks than normal. This has been shown using fMRI and mPASAT. It has been shown that practice makes perfect and it is in fact possible to rewire the brain.
Sleep is usually abnormal with intrusion of alpha waves, altered hormonal releases and lowering of NK cell count. There is also a decrease in exercise induced pain threshold.
Gene studies are very exciting. 35 genes have been differentially expressed, which relate to T cell activation, and neuronal and mitochondrial regulatory abnormalities. Up to 6 subgroups have been identified. ME/CFS is a complex illness and the subgroups must be further defined.
Many treatments were discussed:
Immunomodulatory: Ampligen
Isoprinosine,thalidomide,antiTNF?, monoclonal antibodies.
Autologous lymphocyte study
Antimicrobial: Antivirals such as foscanet, valganciclovir
Endocrine: Florinef (failed when used alone)
Erythropoietin (very modest benefit)
Autonomic: Beta-blockers to regulate the pump
HPA drugs (not particularly useful)
Sleep: Sleep routine
Tricyclics
Sodium oxybate (must have sleep study to eliminate apnoea)
Pregabilin
Melatonin (mixed results)
Cell metabolism
CNS directed medication
Nutrition: CoQ10. ?lipoic acid, NADH etc
Reconditioning: Short 5 minute spells of upright exercise, followed by 5 minutes of flat flexibility work can be more manageable
Exercises to increase flexibility and muscle bulk should be encouraged.
Studies of gene expression using micro-array techniques will help direct us to which drugs will be suitable for which sub group, with the eventual aim being a preventative approach. Quality of life is improved with a multidisciplinary approach and compassionate care.
Dr Jo Nijs (Brussels) then gave an overview of intracellular immune dysfunction in ME/CFS. He described dysregulation of intracellular immunity and upregulation of the RNaseL pathway (due to proteolytic cleavage of native RNaseL), and immune cell apoptosis. The virus in a cell leads to release of interferon, with change in the activity of the host cell, affecting the enzymes, (PKR, RNaseL). Apoptotic neutrophils are increased, leading to cell suicide, which is overactive in ME/CFS. TNF? receptors are increased, RNaseL cleavage is equivalent to caspase activity and there is G-actin cleavage. There is an interplay between NK cells and infections. Conflicting data of the functioning of the PKR enzyme in the blood cells may reflect stages of the illness or distinct subgroups.
The clinical importance of this is a reduction in quality of life and a reduction in exercise capacity, both of which are affected by intracellular activity. Elastase over- activity maybe an important consideration and neutrophil elastase inhibitors may prove useful, as elastase may only be important and needed when the body is fighting massive infection. Drug trials are needed in combination with exercise intervention, as drugs may diminish the side effects of exercise intervention, leading to improved effectiveness. Drugs to fight exercise-induced oxidative stress and subsequent post-exertional malaise may prove useful. Drugs targeting the 2.5A synthetase/RNaseL pathway in combination with careful exercise intervention may also be of future interest.
Dr Gregor Purdie (Scotland) as a GP advisor to the NHS, looked at the development of clinical services for those with ME/CFS. He stressed that knowledge comes from patient contact. There has been some positive progress this year. There is still a great need for clinical services, education and training. Research should be supported and translated into clinical tools. We need to ask ourselves who is to do this, when and how? In the current pyramid of care, with primary care at the bottom and specialist tertiary care at the top, most effort is currently seen at the bottom rung, with much of the work being done by voluntary organizations. Work needs to be done at all levels: local, regional, national and international. The personnel involved should include a multidisciplinary approach with specialist consultants, GPs, nurses, physios, OTs etc. All have a niche role and the eventual aim should be for specialist Centres of Excellence for this perplexing and difficult illness.
Dr Byron Hyde (Ottawa, Canada) looked at various patient-centred research and clinical aspects and presented his view that ME and CFS are not the same thing. He described ME as resulting from chronic brain injury, usually as a result of infection, often during an epidemic. The injury is measurable and most often in the limbic area. He demonstrated with a number of brain scans.
The long viral phase of herpes and EBV has been studied and he feels these are not likely to be the primary cause of the illness. Echo viruses maybe more important. Echo viruses have been recovered in some patients up to 3 years after falling ill. In another study in 2008, he found that Hepatitis B vaccination led to 22% of cases of ME. Mention was made of the high incidence of enteroviruses in China now. In another study, he found that mercury, lead, zinc, copper and aluminium were elevated in 11 out of 53 patients.
Generally patients suffered poor sleep, which led to poor short term memory and inadequate production of human growth hormone. Only 1 out of 53 of patients had a normal sleep pattern with resultant normal brain scan. Brain oxygen saturation was generally low at 88% or less.
He concluded with a case study of an Olympic athlete who seemed to have classical ME, and was eventually found to have a tumour in the atrium. He used this as an illustration of the importance of thorough investigation.
Dr Derek Englander (New York) looked at treatments targeting the methylation cycle. The methylation cycle is complex and a part of general metabolism. He presented a most complicated slide to demonstrate to us just how complex is the biochemistry associated with this illness. His team has developed a protocol over the past 15 years after treating 800 patients, 65% of whom have benefitted. Initially weekly IM injections of kutapressin were used. It was subsequently theorized that there was a defect in the methylation cycle, which maybe due to a genome defect. A wider protocol has now been developed using glutathione, B vitamins, zinc, magnesium, and a number of amino acids.
Dr Gavin Spickett (Newcastle upon Tyne) discussed the care pathways adopted in clinical practice in the North of England. This is based on medical assessment and therapeutic intervention. The NICE guidelines are used for referral, but there is no preferred treatment model, which is to be regularly reviewed. The diagnosis is one of exclusion, looking at other causes of fatigue, such as infection, connective tissue disease, auto-immune disease, sleep problems and organic brain disease. There is overlap with IBS, POTS, FM, overtraining etc. Everything is being stored on a database. Medically experienced physicians are needed as are specific treatment protocols. There is a referral pathway for GPs and there is encouragement to refer children early (at 6 weeks). Pre-screening blood tests are recommended to eliminate other causes, such as coeliac disease, which has been found to be common. Despite this, 17% patients are still found to have other conditions. Older, retired patients need more intensive investigation looking for other conditions.
To increase awareness a number of GP training days were set up and there was no uptake initially, but now these are heavily subscribed.
Of note, 57% of patients relapsed with graded exercise.
Dr Julia Newton (Newcastle) discussed clinical studies focusing on autonomic issues, with particular reference to heart rate and BP regulation. Autonomic dysfunction is strongly associated with fatigue in many ME/CFS patients. There is a problem of synchronicity between the sympathetic and parasympathetic systems. 90% ME/CFS patients have Orthostatic Intolerance (OI). The higher the OI score, the greater is the fatigue. 52% patients experience a drop in BP on tilt table. MRI scans have shown that there is impaired proton removal from muscle during exercise in patients, so it is hypothesized that the fatigue arises due to impaired pH run-off from muscle during exercise., which maybe influenced by the autonomic dysfunction. Research is now focusing on how to help patients reset the parasympathetic/sympathetic balance.
Annette Whittemore, (Nevada,USA) who is president of the Whittemore-Petersen Institute for Neuro-immune Disease was unable to be present, so her address was given on her behalf by Dr Dan Petersen (Nevada). This exciting development is to be a centre of excellence comprising 80,000 sq ft at a cost of 78million$US. It will be a comprehensive patient-friendly research facility devoted to patients with neuro-immune diseases such as ME/CFS, FM, atypical MS and other similar presenting illnesses. Location is within the Centre for Molecular Medicine, University of Nevada. Research is already being established and currently looking for bio-immune markers which could lead to more effective treatments , and also looking at those ME/CFS patients who go on to develop cancer.
Dr Dan Petersen then gave an overview of the current research taking place in Nevada. He began by telling us that in the US 10% of the patients consume 70% of the healthcare dollars, and chronic disease diagnosis and management accounts for a significant proportion. Patient-centred, cost effective approaches are being designed and implemented.
Oxidative impairment is evident in ME/CFS and there is a need to demonstrate this to insurers. Exercise tolerance testing with expired gas exchange is widely recommended, but paired tests are needed as performance is significantly decreased on the second test over a 2-day interval. Other research to be furthered will be identifying subsets, looking at the role of viruses in the development of neoplasia in chronically affected patients, looking at bone marrow as a reservoir for HHV6 as PBMCs rarely show HHV6, and collaborative studies utilizing viral array to identify potential patients who may be amenable to specific antiviral therapy will be undertaken.
One study presented analysed cytokines and chemokines in a controlled trial and found chemokines dramatically high with Th1/Th2 dysregulation. These patterns may prove useful diagnostically and potentially therapeutically. The specialized field of Informantics is being utilized to analyse and manage complex inter-relationships involving multiple variables longitudinally.
Vascular and inflammatory aspects of ME/CFS were presented by Dr Faisel Khan (Dundee). There is increasing evidence that ME/CFS patients have associated cardiovascular symptoms. Endothelial function is an important regulator of vascular function and a well established marker of cardiovascular events. ME/CFS patients have significantly enhanced vascular responses to acetylcholine (ACh) compared with control subjects. This may be a consequence of free radical attack on acetylcholinesterase expression on the vascular endothelium, giving rise to a reduced expression of the enzyme, resulting in the prolongation of the ACh response.
Arterial stiffness is also significantly elevated in ME/CFS compared to controls, and this is associated with elevation of CRP, pointing to low grade inflammation and oxidative stress. All this may result in unfavourable haemodynamics and increased risks of cardiovascular events in ME/CFS patients. Increased arterial stiffness and inflammation maybe regulated by levels of Vitamin D. Other risk factors for ME/CFS patients may be a tendency to lower HDL cholesterol and higher LDL.
Isoprostane is a marker for oxidative stress, and in ME/CFS this goes up with exercise intolerance. Oxidative stress can lead to endothelial damage.
Dr Jonathon Kerr (London) gave a review of the molecular studies in ME/CFS at his centre. 88 genes have been identified of which only 3 were down-regulated the others were all up-regulated. The highly represented functions were haematological disease and function, immunological disease and function, cancer, cell death, immune response and infection. 13 transcription factors were over-represented. Data from ME/CFS patients revealed 7 subtypes with distinct differences in SF-36 scores, clinical phenotypes and severity. 12 genes have been linked with EBV. It is now important to determine what these subtypes represent as they appear to be biologically meaningful. Possibilities for treatment with 5 potential drugs to target these genes should provide rationale for treatment. The study needs to be confirmed and replicated, and specificity of the genes needs to be tested. Eventual diagnostic test subtyping should be possible.
Prof Birgitta Evengard presented her teams work with the Swedish Twin registry looking for a biomarker. 31.406 individual twins, comprising 12,407 complete pairs, responded to a telephone interview and 1 in 5 claimed to be tired. 2.36% had fatigue with symptoms suggestive of CFS of at least 6 months duration. 33 pairs of monozygotic twins discordant for CFS were identified. 1779 individual twins were identified for ongoing study. There was no sex difference in symptoms, but the females had more severe symptoms. There was no association with age, education or occupation. The mean number of symptoms was 2.4. The commonest symptoms were sleep difficulties, cognitive impairment, myalgia and joint pain.
Estrogen may be the key regulator. It is a regulator of growth and differentiation in the reproductive tract, breasts, CNS` and skeletal system. Alpha and beta Estrogen (ER? and ER?) receptors are implicated in several diseases. There was reduced expression of ER? in patients consistent with immune mediated pathogenesis in CFS. There was also HPA axis disturbance, immune dysfunction (with abnormal cytokine dynamics), abnormal blood/brain communication and a background of infection. 75% improved with valganciclovir. Genes were identified in 20 of the women and 2 more viruses were detected (orphan viruses).
Q fever, Rickettsia and CFS was the topic discussed by Dr Stephen Graves (NSW, Australia). Rickettsia are gram negative bacteria transmitted by arthropod vector. They were named after Ricketts the microbiologist, and are nothing to do with rickets due to malnutrition. Patients respond in different ways:
Death
Infection, then recovery
Auto-immune illness
Chronic Fatigue Syndrome.(10-20%)
Illness due to Rickettsia honei and Q fever caused by Coxiella burnetii both have similar sequelae.
CFS is largely a post-infectious condition, and Q fever and Rickettsia can be precipitants. The microbial antigen may persist. These bacteria have an intracellular lifestyle. Post Q fever the microbial antigen persists in the bone marrow and PBMCs. The microbe C,burnetii is not viable because a cell mediated response has killed it, but it may persist as undegraded cells with some DNA. The antigen is only found in the more virulent form. The persistence of the microbial antigen appears to cause dysregulation of the cytokine cascade leading to ongoing fatigue in a genetically predisposed subpopulation. The relevance of this could mean that Q` fever vaccination could have a positive impact on the incidence of CFS in Australia.
As always when a conference ends, there is a sense of sadness saying goodbye to old friends again, but innevitably a great sense of excitement and hope at the progress and new ideas. Thank you to Vance Spence and Neil Abbott, and their Irish counterparts for the brilliant organization of this wonderful event, which I felt privileged to attend in such a lovely English setting. And, many thanks also to ANZMES for enabling me to participate.
Rosamund Vallings MNZM, MB BS
Filed under: Conference Reports & etc.
July 4, 2008 • 9:50 am Comments Off
Webcasts of all ten presentations have now been added to the Royal Society of Medicines website. These also include PowerPoint slides which accompanied the presentations.
For ease of reference, all links to webcasts are collated in this one posting, together with links for the ten presentation document PDFs. Those on dial-up internet access please note that the PDF for Sir Peter Spencers presentation is around 6.0MB file size.
The webcasts are available in four session sections. Registration is required to view these webcasts but this does not take long to fill in and is processed immediately – you may need to log in each time you return to the site.
Links provided by ME Agenda
Filed under: Conference Reports & etc.
March 13, 2007 • 2:09 pm Comments Off
The 8th IACFS conference was held in January 2007. CFS PHOENIX have provided several web pages of information from this conference.
From the Patient conference:
From the Professional conference
Filed under: Conference Reports & etc., Notice Board
September 16, 2006 • 12:28 pm Comments Off
On Friday 8 September at 7:30pm in the Conference Room at the Abel Tasman Hotel on Willis Street, Wellington, Dr Nancy Klimas gave a presentation on “Research Advances In Chronic Fatigue Syndrome”. She covered the background science/immunology of the illness in light of
the current research, and talked about diagnosis and management.
Dr Nancy Klimas is a leading Immunologist from Florida,is President of
the International Association for Chronic Fatigue Syndrome, and a world
renowned researcher/clinician on CFS. She is based at the University of Miami (biography)
“I have heard Nancy talk at several conferences. She is an excellent speaker
and all her work is strictly evidence based. Although she is a very high
powered person, her pitch is very easy to follow even for the non
immunologically inclined. In fact many comments from her previous
presentations from other doctors have been that it was the first time they
really understood immunology!” Dr Rosamund Vallings MB BS
A DVD of this presentation is available from the groups library, or you can purchase your own copy for $10 (postage free in New Zealand), by contacting Martin.
A Powerpoint slide-show that accompanies the talk can be downloaded here.
Filed under: Conference Reports & etc.
July 28, 2004 • 3:50 pm Comments Off
Three different diagnostic labels (CFS, Nightingale Disease and ME) were used in an interesting study presented by L Jason to determine their effects on the attributions of medical trainees and undergraduates regarding CFS. Medical trainees viewed the CFS label as the most accurate based on the case history described, the ME label was associated with the poorest prognosis. When labelled ME, the undergraduates however were more likely to attribute a physiological cause to the illness coupled with decreased potential for organ donation.
The role of interpersonal violence history and PTSD diagnosis in Chronic Fatigue and CFS was discussed by R Taylor (Chicago). Although there was a higher prevalence of these conditions in the histories of those with different types of Chronic Fatigue, there is no greater incidence in those with CFS compared to other fatiguing conditions.
It is apparent that there is no relationship between the number of medically unexplained complaints such as chronic pelvic pain, chronic fatigue, back pain and tinnitus and psychopathology, according to a study presented by L Tiersky (NJ). The DIS was used to determine whether CFS patients had a psychiatric diagnosis following development of CFS as well as any lifetime history.
A Lyden (Washington DC) found a subset of individuals who began to experience CFS-like symptoms when they are not performing regular exercise. Baseline measures were taken before symptom development and there were differences in autonomic and HPA axis hypo- responsiveness, which are typically observed in those with established CFS. Symptoms developed following 7 days exercise cessation. This study may indicate that some individuals have a vulnerability to developing CFS according to their endocrine profiles.
P Fennell (NY) presented a study testing the validity of the Fennell Phase Inventory to measure the phases typically experienced by those with CFS. The phases are: crisis, stabilisation, resolution and integration. This instrument was found to accurately differentiate the phases of adaptation to the illness.
A plane crash in the area of Bijlmer resulted in a number of local people experiencing health problems. E Van Hoof (Brussels) presented data suggesting these complaints were similar to CFS and Gulf War illness. 67% were found to be infected with mycoplasma.
Type of onset was considered by D Cukor (NY) looking at whether those with sudden onset would have more psychopathology, somatic complaints and more circumscribed complaints that the gradual onset group. There was however no correlation and this study questions the utility of distinguishing CFS patients according to type of onset.
A Donnay had looked at whether carbon monoxide poisoning may play a role in the aetiology of CFS, FM and multiple chemical sensitivity. He found that those with these conditions did have an increase in end-tidal breath CO, which was enough to distinguish them from healthy controls, but not from each other. He therefore questioned the possibility that these patients may have been affected by exogenous CO. However he postulated that it is possible that the increased levels maybe due to endogenous CO derived from routine breakdown of heme proteins.
Functional status in CFS patients was assessed by K Busichio (NJ) using the community integration questionnaire (CIQ). This has provided valuable information regarding daily functioning in CFS. Those who are unemployed due to health problems demonstrate less community involvement and are generally less productive inside and outside the home than employed subjects. Physical rather than psychological factors contribute more to lower daily functioning.
J Baraniuk (Washington DC) showed a poster looking at Multiple Chemical Sensitivity (MCS) using a MCS questionnaire. 4 respiratory responses (cough, runny nose, shortness of breath and rhinitis) were found to have the power to predict positive responses and CFS status. 42% patients with CFS were found to suffer MCS compared to 3.8% controls. Clusters of substances most associated with the symptoms were: volatile organic compounds or fine particulate materials. Medication-related symptoms were common in women with CFS but not other groups.
Fibromyalgia patients and healthy controls were shown to have very consistent ratings for the whole range of pain perception in an ascending paradigm. The findings presented by R Gracely (Washington DC) do not support an exaggerated affective response in experimental pain in CFS.
35 Danish CFS patients were found to suffer severe social isolation,with none reporting a return to pre-morbid functioning after 5 years, in a poster presented by F Albrecht (Maryland). Two reported that they were performing close to normal work and social life. Most reported deterioration in social and familial contact and entertainment. These results do suggest that CFS produces severe functional impairment and substantial recovery is uncommon.
A Peckerman (NJ) confirmed that living with CFS is highly stressful, but results of the study are more equivocal regarding the view of CFS as a stress disorder. In CFS the stress is not attributable to inefficient coping skills and does not appear to affect symptoms adversely. However those who acquired the illness after Gulf War service do seem to have problematic coping strategies. Results suggest that learning more adaptive coping skills maybe a useful adjunct to management in both Gulf War Veterans with CFS.
Traumatic and negative life experiences at any time in one’s life leave one prone to attribute the illness to a psychological cause, according to a poster presented by K Busichio et al (NJ). It seems likely that the earlier life events can leave one vulnerable to psychological attributions. Different treatment approaches may therefore be needed for these patients, as this may impact on the progression of the illness. In a second poster by the same team, participants’ attributions about their illness paralleled the type of disability reported. Belief that the illness was physical in nature correlated with overall and specific decreases in physical functioning, while psychological attributions were related to issues such as motivation. Illness attributions can be an important issue in formulating a treatment plan. Their 3rd poster found that traumatic and negative life events do relate to dysfunction in CFS. Using the SF36, physical functioning correlated with the occurrence of any traumatic experiences and with negative life events during the onset of CFS. The Mental health Index correlated with negative life events during and after the onset of CFS. Pain index correlated with occurrence of any traumatic experience. The timing of events may relate to specific areas of future disability.
The group also looked at the issue of malingering, using measures to estimate whether in fact those with CFS had neuropsychological impairments as a result of lack of effort during testing or attempts to feign impairment for financial gain. No subjects were found to be performing sub-optimally on a measure of effort, however subjects who reported more cognitive difficulties performed worse on the test, showing that those with cognitive difficulties put less effort into testing though this was not considered significant.
Psychiatric co-morbidity and symptoms in fatiguing illnesses was studied by E Axe (Los Angeles) and it was found that only 3 of 14 CFS-related symptoms were associated with psychiatric disorders such as major depression or a somatization disorder. These symptoms were cognitive complaints, sleep disturbance and headaches. Treating these symptoms therefore could have a positive effect for those patients who are depressed.
There were 2 posters by the team in Newcastle (NSW) presented by N McGregor. The first was an analysis of serum lipid changes associated with fatigue, muscle pain and different factor symptom groupings. Results suggested that each measure represents a distinct change in lipid chemistry. It was further suggested that investigation of lipid metabolism and low fat diets in the treatment of CFS patients is warranted. The 2nd poster also looked at symptom clusters. The different factor groupings were associated with changes in red cell oxidative marked parameters, suggesting that each measure represented a distinct change in chemistry.
P Soetekouw (Nijmegen) studied 25 patients and 25 controls to assess carnitine levels but found no significant differences in levels of total carnitine, free carnitine and 20 carnitine esters between CFS patients and controls.
Skeletal oxidative damage was observed in CFS patients by D Racciatti et al (Chieti, Italy). This was thought to be a consequence of imbalance between an abnormal production of reactive oxygen species (due to oxidative metabolism related to mitochondrial activity) and a disabled scavenger enzyme system. This data supports an organic origin of CFS.
K Rowe (Melbourne) reviewed the symptom patterns occurring among 189 adolescents with CFS. Fatigue and headaches were found to be the most frequent symptoms, followed by sleep problems, cognitive difficulties and myalgia. 85% had had a viral or febrile onset. From the responses to a 38-item, well-validated symptom questionnaire, 3 subgroups could be identified on a severity basis. The most severe group had more pain and fatigue, the moderately severe group had more neuro-cognitive symptoms and the least severe group had more headache/nausea and abdominal pain.
In her second paper, Rowe had followed up 200 young people with CFS seen in a specialist clinic with illness duration from onset ranging from one to ten years. Average duration of illness at follow up was 38 months. The severity of illness had no effects on the duration of illness, but the most severe group had taken the longest to reach a diagnosis. Depression was linked to severity of illness and occurred in 7%. 76% had found professionals who took them seriously and provided management strategies, symptom relief and emotional support were helpful. Of the 70% who had tried alternative therapies, less than a third had found at least one therapy that had helped, and most thought these approaches a waste of money. 30% considered they were well with 60% able to function in full-time study or work. Early diagnosis, implementation of management strategies and flexible school arrangements eased many of the burdens of chronic illness. During recovery, the symptom that tended to go first was headache followed by fatigue.
D Bell (Lyndonville) had also followed up 35 children and adolescents with CFS thirteen years after illness onset. Average age at onset was 12 years and 77% had gradual onset. 13 (37%) of the children considered themselves resolved of illness, 15 (43%) were well but not resolved, 4 (11%) considered themselves chronically ill and 3 (8.6%) considered themselves worse. 8 (23%) had missed more than 2 years of school and 5 of these were still ill at follow up. The amount of school missed correlated with illness severity at follow up and perceived social impact of the illness. The time of resolution was between 1 and 9 years, and this was often a very gradual process. Those who missed the least school made the best recovery. There was no correlation between age of onset and level of recovery.
Work looking at vascular perturbations in CFS in adolescents in relation to chronic orthostatic intolerance was presented by J Stewart (NY). He found that leg circumference tends to be larger in CFS patients on standing, and resting venous pressure was higher in CFS than controls. Data also suggests that the threshold for oedema is lower and filtration is increased. These findings make CFS patients particularly vulnerable to dependent pooling and oedema. This may imply a redistribution of blood to the lower extremities even when supine, accounting for tachycardia through vagal withdrawal.
M Scott Smith (Seattle) compared adolescents with CFS and migraine. Those with CFS were found to have far greater functional disability than adolescents with migraine or controls, but did not report higher levels of anxiety or depression. In both CFS and migraine, somatization scores were higher than in normal controls.
Adaptive coping styles do not seem to improve symptom severity or improve perceived self competence in adolescence, according to a study by D Bell et al (Lyndonville). Increased social support is helpful in the area of perceived self competence.
S Hoogveld (Nijmegen) found significant differences in personality profiles of adolescents with CFS compared to controls and this might indicate a higher vulnerability to internalising problems. These young people were described by parents as being more ego-controlled, more conscientious and less extrovert than controls. Emotional stability was often lower, but parents described their CFS children as more agreeable.
The first presentation in this session was by D Williams (Washington DC). He had done a randomised controlled trial of CBT in fibromyalgia (FM). 2 groups were assigned: standard medical treatment coupled with aerobic fitness instruction or CBT plus standard medical care. CBT was given over 6 sessions. Of the CBT group, 25% achieved improvement in physical functioning at 12-month follow up, while 12% of those in the standard medical group achieved the same level of improvement. This represents a 48% improvement with the addition of CBT, and this finding supports the inclusion of CBT as an essential component in standard treatment procedures for FM.
The efficacy and safety of modafinil for the treatment of fatigue in Multiple Sclerosis (MS) was discussed by K Rammohan (Ohio). Modafinil is described as a wake-promoting agent shown to be effective in narcolepsy. 200mg daily was found to significantly improve fatigue and daytime sleepiness in a study of 72 MS patients. It was well tolerated, though side effects were more common at 400mg, and at this higher dose there was no extra improvement noted. This drug may be a useful addition to the pharmacological options available to treat fatigue associated with MS and other fatiguing conditions.
K Rowe (Melbourne) presented a 7-year follow up of 58 young people with CFS who were involved in an IV gammaglobulin trial. There was continued improvement in functioning with 75% able to work or study full-time. 17% still described themselves as disabled. A small percentage had relapsed or experienced exacerbation of symptoms, and the occurrence of other serious illnesses was not greater than could be expected by chance.
D Cox (London) described the inpatient occupational therapy intervention for CFS at Romford, Essex. The principles of CBT and graded activity were applied to this very ill group of patients. At 6 months there was no significant change in symptoms or ability level, but there was a significant effect on the patients’ perceived health, length of time tired and management of the illness, with 72% of the inpatient group, compared to 44% of the comparison group, stating that they felt better and felt the illness was being managed better. It was found wise to limit the hospital stay to no more than 6 weeks, as transition back to home would then prove more difficult. Age had no significant effects on outcome, although those who had been ill for less than 5 years did better.
A pilot study of tumour necrosis factor fusion protein, etanercept (a substance which blocks the interaction of TNF with its cell surface receptors) was done by K Lambrecht et al (Minneapolis). 6 CFS patients were given an 8 week trial of etanercept injections. Significant reductions were observed in the severity of fatigue, muscle pain, headache and lymphodynia. Exercise tolerance was improved. This lends support to the theory that proinflammatory cytokines maybe involved in the pathogenesis of CFS, and this should be further studied in a placebo-controlled trial.
A safety and feasibility study of immunomodulation using lymph node extraction, ex vivo cell culture and autologous cell reinfusion by N Klimas et al (Miami) found a lack of adverse effects, coupled with favourable clinical results. 13 patients were studied of which 2 had unsuitable nodes. The remaining 11 all underwent the procedure successfully with significant positive clinical outcome over 24 weeks. An improved cytokine shift correlated with clinical improvement, and this holds weight to the idea that increases in cytokines lead to symptoms. At 18 months, improvement is sustained. Further clinical trials seem warranted.
T Emms (Newcastle NSW) presented data suggesting that food intolerance as opposed to allergy may represent co-morbidity in a subgroup of CFS patients, and this could have implications for development of gastro-intestinal dysfunction. It was suggested that clinicians should trial a treatment protocol involving dietary history coupled with elimination diets.
Longterm nutritional supplementation was shown by K Dykman (Texas) to have some positive effect on the general functioning in FM/CFS patients. Glyconutritional products and phytogenins were used. Polynutrient supplements were also trialled by F Brouwers et al (Nijmegen) and no significant differences were found between placebo and experimental condition.
Downregulation of Th2 cytokine production with a shift to Th1 cytokine expression was suggested as a useful intervention in CFS by R Partarco (Miami). Past approaches have been based on the use of Staphylococcus vaccine, influenza and/or rubella vaccines and autologous reinfusion of expanded lymph cells. Further studies are needed to allow elucidation of factors that mediate Th2-type cytokine expression predominance and maintenance.
G Whalen (Washington DC) considered the issue of autonomic dysfunction in CFS, and compared immune and cardiac responsiveness to beta-adrenergic agonist infusion (using isoproterenol) in CFS patients and controls. No differences were found, suggesting that there are no differences in afferent sensitivity to beta-adrenergic receptor occupation in this illness.
C Van der Eb (Illinois) designed a college course experience for students and their partners with CFS. Field work involved one-to-one support by the student with a person with CFS (a buddy system). The students were involved in a community-based learning programme educating them about the realities and personal costs of such an illness. This provided much needed, individualised support for those with CFS.
The use of ampligen in CFS by C Snell (Philadelphia) in 2 women with CFS led to some improvement in quality of life , decreased pain, enhanced energy levels and improved cognition. Ampligen intervention was also looked at from the economic point of view by A Shillington (Illinois). A pharmacoeconomic analysis was performed on data collected from 92 patients with severe CFS, who were randomised to a double blind, placebo-controlled trial of ampligen. A twice weekly infusion of 400mg ampligen over 24 weeks was found to significantly reduce the consumption of valuable health resources, and thereby reduce the costs of treating CFS. The therapy was well tolerated. A poster by D Strayer (Philadelphia) also showed considerable benefit from the use of ampligen as measured by Karnofsky scores and cognitive function data. 41 severely debilitated CFS patients were treated with the majority continuing treatment beyond 24 weeks. In his 2nd poster, he compared twice weekly with thrice weekly dosing with ampligen , and found that the thrice weekly dosing offered no advantages.
Midodrine (a peripheral alpha-antagonist) was used with some improvement in adolescents with orthostatic intolerance and CFS by M Alexander (Boston). Serious side effects seem uncommon and this drug can be a useful adjunct for management. If fludrocortisone is used concurrently, there is a small risk of hypertension.
Group CBT for 31 patients with CFS was compared to a waiting list control group of 35 CFS patients by G Bleijenberg (Nijmegen). It was found that CBT had a positive effect on fatigue when compared to the control group, but differences on outcomes concerning functional impairment were opposite to what was expected, in that those in the control group improved while those on CBT remained the same.
On the final afternoon of the conference, the current state of our knowledge and various aspects of underlying pathology, diagnosis and management were summarised:
The issue of pain in fibromyalgia (FM) was considered. Many syndromes are associated with FM such as irritable bowel syndrome, and the generalised pain threshold is low. Patients have an increased sensitivity to noxious stimuli, but normal detection threshold to touch. Likely mechanisms are: expectancy, hypervigilance or central changes in nociceptive processing, which is more physiological. Physiological mechanisms seem to be more prominent than psychological. The problem seems to be at the level of the cord or brain and not at the skin. Levels of substance P are 3-4 times higher in the spinal fluid in FM, and MRI studies show changes when the patient is experiencing pain. i.e. we are looking at a sensory processing defect.
Various types of brainscanning were reviewed. On MRI there are small areas of high signal in the white matter, and although many of these are seen in healthy controls, all studies have shown an increased number in those with CFS/FM. (80% in patients, 20% in controls). SPECT scans are more physiologic and show a “tattered” signal in CFS. A functional MRI gives a better picture of the physiology. The brain appears to be working harder than in a healthy person doing the same task. Other parts of the brain seem to be brought in to “help”.
Abnormalities have been found in both the parasympathetic and sympathetic nervous systems. In the neuro-endocrine system, the hypothalamus is disordered, with disruption of ACTH stimulation and abnormalities in prolactin and growth hormone.
History taking is an important part of making a diagnosis of these disorders. One needs to consider whether the illness occurred as a result of an infectious on non-infectious event. History of all the following need to be considered: blood transfusion, surgery, febrile illness, toxic exposure, bites or stings, stress, trauma, foreign travel, STDs, sleep patterns, dental problems, ownership of pets or birds, immunisations, pregnancy, bleeding gums, sinus and respiratory infections, TM joint dysfunction etc.
First level of testing should include: full blood picture, IgE, intracellular RBC magnesium and serology, ECG including an exercise test. (The U+T wave is often big, and may look like a prolonged UT segment), chest Xray, abdominal ultrasound and further tests depending on specific symptoms e.g. panoramic Xray of dental roots, pulmonary function testing.
Second level of testing, much of which could only be done in a specialised laboratories (such as in Brussels) would include: LMW RnaseL/actin fragments, swabs to check for toxin producing coag uve staph aureus, immunophenotyping (total lymphocytes, activated T cells, CD4/CD8 ratio, NK subsets etc), antithyroid antibodies, immunoglobulins, Th1/Th2 profile, TNFalpha, interleukin 1, PCR for mycoplasma, chlamydia etc., hypoglycaemia test ( looking at ACTH, GH, cortisol, prolactin after injection of insulin), polysomnography in males over 35 (for sleep apnoea), neuropsychiatric evaluation.
It was pointed out that many physicians would not have access to these specialised tests, and also much time would be needed, particularly for tests such as a full neuropsychological investigation, which could take 3 hours.
10% of the population have widespread pain, females more so than males. The prevalence of FM is 2%. There is no diagnostic test. The more tender points, the greater the distress. The more constant the pain, the more likely the diagnosis is to be FM. The pain is achy and generalised, and waxes and wanes. 30% patients reviewed recently had an active mood disorder. Patients usually feel drained with a poor sleep pattern, headaches and concurrent irritable bowel is common.
Examination reveals the typical tender points, with no evidence of muscle or joint disease. (NB if the thumb nail blanches, one is applying adequate pressure). Lab investigations show normal acute phase reactants (ESR,CRP), muscle enzymes and thyroid function. Treatable disease must be excluded, such as sleep disorder, subclinical hypothyroidism, ankylosing spondylitis. One cannot rely solely on the tenderpoint examination and FM can co-exist with other conditions. FM does not respond to prednisone, so benefit from this may indicate a condition such as polymyalgia.
We are looking at a heterogeneous population with lack of objective diagnosis. Few treatment trials have been done, and there is an absence of objective response markers. Newly diagnosed cases may be quite different from long-standing cases. For correct management a diagnosis is vital. Many hypotheses for therapeutic intervention exist, and a wide range of drugs have been tried such as: calcium channel blockers, psychoactive agents, opium antagonists, immune modifiers, antidepressants, stimulants etc.
Sleep impairment is an important area of treatment and may respond to tricyclics or clonazepam. Antidepressants do appear generally beneficial. Cortisol has been shown to have no benefit and may cause adrenal suppression. A trial with low dose hydrocortisone showed some mild benefit, but this is not generally recommended. For those suffering neurally mediated hypotension, treatment maybe helpful. In a study using of galantamine, an acetylcholinesterase inhibitor, there was no significant benefit. Growth hormone showed minimal help. CBT has been found to be better than just standard practice. Most people who have tried NADH have not been helped, though a small percentage did improve in one study. Neither treatment for allergies or use of antifungals have been found to be helpful. Some studies have shown evening primrose oil to be useful, but echinacea is of no help. Surgery for Chiari syndrome is rarely of use. There is some evidence that some antivirals can be of use, when viral pathology is implicated.
There is often maladaptive illness behaviour with psychiatric co-morbidity, issues of secondary gain, general distress etc. as opposed to physiologic factors, but the greater the physiologic factors, the more likely the behavioural problems will develop.
Some drugs will raise the concentration of anti-nociceptive compounds. a) descending pathways: tricyclics, SSRIs, new MAOs. b) opioids c) GABA d) cytokines (no suitable drug) e) CRH. We know of no drugs to lower the concentration of pro-nociceptors, except possibly dextromethorphan.
Treatment approaches should include: education, pharmacology (tricyclics for sleep, symptom based therapy such as tramadol for pain etc.), aerobic exercise (which should begin after pharmacological approach to reduce pain), CBT to reduce maladaptive behaviours in a stepped approach and some complementary therapies (acupuncture, biofeedback/relaxation, physical modalities).
A 4 phase model of CFS was outlined by P Fennell using the Fennell Phase Inventory: crisis, stabilisation, resolution and integration. During each phase, 3 domains were important: physical/behavioural, psychological and social/interactive. For each domain in each phase, medical assessment and intervention and phase assessment and intervention were discussed. A very useful protocol was provided in a handout, which would be important for physicians, psychologists, social workers and other professionals dealing with CFS. D Uslan enlarged on some of the detail, and much discussion ensued regarding this important multi-dimensional approach to management.
Education of physicians was considered really important for the benefit of all CFS patients and a co-ordinated team approach seems the ideal.
(CDC and prevention planning session)
An open forum discussed this issue before the conference officially began. The actual definition of fatigue was covered. There are many parameters of fatigue (e.g. the fatigue in cancer is quite different to that in CFS) and the question was asked “Is fatigue the right way to identify these patients?”. One needs to be able to qualify and quantify fatigue. As yet there is no “perfect” definition of fatigue.
N Klimas pointed out that we should not refer to the definition as the CDC definition but the International Consensus definition. There is confusion between the research and clinical definition, and the current definition refers to the research case definition. She went on to say that fatigue has much ambiguity, such as physical and mental, frequency, duration and level etc., and the exclusion criteria are vague, e.g. obesity, depression.
L Jason talked of the standardisation/operation of the classification instruments. CFS patients are more functionally impaired than, for example those with diabetes. One needs questionnaires on various aspects of the illness. There are also a number of overlapping syndromes. Useful measures are the sickness impact scale, medical outcome scale, sleep assessment questionnaire, fatigue severity scale, Beck depression inventory, scale of fatigue (Australia) and SCID and DIS for assessment of psychiatric co-morbidity. Onset, severity and phases of illness need to be established.
Study design was discussed by S Vernon (CDC). There is often a lack of the number of symptoms at particular times in the illness, and this may relate to its waxing and waning character. There are problems in the absence of a specific lesion. Systemic blood needs to be used in the hope to find molecular markers.
W Reeves said that as the current definition was developed by consensus we need to empirically define CFS, The 1994 guidelines are driven by “fatigue”. There is no single marker for CFS, so it is necessary to decide which symptom complex best defines CFS.
Data was collected in a population based study in Wichita looking at the whole community of 27,000. 3500 were found to be fatigued for more than one month, and 46 had CFS. A dichotomous factor analysis of the symptom complexes was performed. Chronic fatigue, weakness and non-refreshing sleep were the factors not differentiating patients and controls. There was some overlap between those who were chronically unwell and those with CFS. These findings were similar to what was found in Gulf War Illness. Very few minority groups were seen.
In summary important conclusions were that patients with symptoms of fatigue need an intensive medical workup, and we cannot do research properly until we have a workable case definition.
This was a lively discussion in which the possibility of name change was addressed by a number of health professionals and CFS patients looking at the issue from many points of view. Names describing underlying pathology such as myalgic neuro-asthenia, neuro-endocrine immune disorder and myo-encephalopathy were suggested, as were names of people who had suffered the illness or researched it, such as Nightingale disease or Shelokov syndrome. Incorporation of place names seemed too specific to particular epidemics: Royal Free disease, Incline village syndrome, Icelandic disease.
General consensus seemed to come down in favour of getting away from Chronic Fatigue Syndrome, and concentrating on the underlying pathogenesis, while retaining something familiar, such as the term ME, which is still widely used in a number of countries. Myo-encephalopathy did fit the bill, but obviously any decision for name change needs to be international and taken with great care to avoid need for further change, which eventually only confuses the issue further and does not work in patients’ best interests.
[This concludes Dr. Vallings' on the Seattle AACFS conference. Please remember, regardless of what you may read in these reports, be sure to consult your licensed health care practitioner about your own health care.]
The conference’s program book with some 130 abstracts is available for purchase:
Checks should be made payable to:
AACFS
c/o Harborview Medical Center
325 9th Ave, Box 359780
Seattle, WA 98104
USA
Allow 2 weeks for delivery.
While no official video tapes were made of the conference’s research and clinical sessions, video tapes are available for the Patient Information Day that followed the main sessions.
click for detailed information or send an e-mail inquiry to aacfsvideo@hotmail.com
There are four separate tapes and they cost about $10 each plus shipping and handling charges. These tapes are provided by the Seattle CFS/FMS Support Group
PO Box 1071
Maple Valley
WA 98038
USA
Although there is no official word from the group, it is likely that the tapes are available only in the North American format and will not work in overseas VCRs.
The information provided on this page is from CFS-NEWS (ISSN 1066-8152) an international newsletter published and edited by Roger Burns in Washington D.C. Copyright (c) 2001 by Roger Burns. Permission is granted to excerpt this document if the source (CFS-NEWS Electronic Newsletter) is cited and the author of each article (when shown) is indicated. Permission is also granted to reproduce the entirety of this document unaltered. This notice does not diminish the rights of others whose copyrighted material as so noted may be quoted herein. All trademarks, both marked and not marked, are the property of their respective owners. The content of this independent newsletter and the accuracy of the sources which it cites are solely the responsibility of Roger Burns.
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Filed under: Conference Reports & etc.
July 28, 2004 • 3:49 pm Comments Off
The American Association for Chronic Fatigue Syndrome (AACFS) held its 5th biannual conference in Seattle during January 25-29, 2001. There were close to 130 presentations in total, including both the oral and poster sessions.
Dr. Anthony Komaroff of Harvard Medical School commented on his view of the highlights of the conference in a talk he gave after the research and clinical sessions were completed. His points are summarized below. Komaroff began by thanking Dr. Dedra Buchwald for her hard work in organizing the conference.
Lea Steele presented a study that addressed the questions of: (1) whether CFS exists among those who meet the Gulf War illness definition; (2) how frequently that may happen; and (3) are there differences between the kinds of CFS seem among Gulf War veterans compared to the CFS seen in the general population. Steele’s group conducted a telephone survey of about 1,500 Gulf War veterans and about 500 non-Gulf War veterans. Steele found a remarkably high prevalence of CFS among Gulf War veterans, about 7% — much higher than in the general population. CFS as found among Gulf War veterans differed from CFS in the general population by more often showing headaches, diarrhea, skin rashes, and night sweats, and the mean age at onset was a decade earlier. So there are differences and similarities.
A CDC study led by Rosane Nissenbaum took advantage of a previous large community survey of Wichita and followed those cases forward in time. Community studies get a broader view than studies limited to only those cases that are referred to a clinic. In the Steele study, 35 out of about 20,000 surveyed had CFS and were followed up. Most had not had been diagnosed by doctors in the community. These patients had a better prognosis than those found in strictly clinic-based studies. In general, the study showed that 18% of CFS cases were clearly better, 20% were clearly improved, 21% were found in fact to have other diagnoses, and 32% had CFS but did not improve.
In a study by Leonard Jason et al., nearly 20,000 people were surveyed in Chicago. A small number had CFS. The issues that were examined were: when we look at subgroups, can we see differences in severity? Indeed, more severe symptoms were found in women than in men, and severity was also greater among minorities and nonworkers. These results reinforce what the CDC and others have found in studies in San Francisco and elsewhere. So CFS is not restricted to affluent young Caucasian people.
Pascale de Becker of Belgium presented a study that compared illness severity among CFS cases as defined by Holmes (1988) vs. those defined by Fukuda (1994). Note that the Fukuda definition removed physical examination features, and many people expected that this change would capture a larger fraction of the general population. Several studies have showed that this is in fact true. Now this study shows that the 1988 definition catches cases that are more severe.
This segment contained mostly studies of the autonomic nervous system (ANS). That is the part of the nervous system that controls many of the bodies vital functions: blood pressure, pulse rate, breathing rate and body temperature. A wealth of studies, perhaps 85%, confirm the original study conducted at Johns Hopkins that found abnormal ANS in CFS. About 40% to 90% of CFS cases have ANS dysfunction. These are small studies from which it is hard to draw firm conclusions.
Three studies presented by Soetekouw, Baraniuk and Peckerman examined various challenges to the ANS. Komaroff said that his own summary view, adding these current studies to previous ones, is that there probably is still no completely consistent picture of the autonomic abnormalities seen in CFS, but there is substantial evidence that both the sympathetic and parasympathetic nervous systems are abnormal.
There was also a new finding presented by Dr. Julian Stewart that one of the consequences of ANS dysfunction is that it may be that blood pools in the legs of CFS patients, thus lessening the amount of blood left in the rest of the body. This suggests many treatment options, such as very tight elastic stockings.
Christopher Snell et al. found a correlation between an abnormal 2-5A system and exercise capability as measured by treadmill tests and use of oxygen. The 2-5A pathway is a series of enzymatic reactions that goes on inside white blood cells when they perceive themselves to be infected by viruses. Whether this happens with other types of infections or stressors does not seem to have been carefully evaluated, said Komaroff. This 2-5A pathway abnormality in CFS has been researched by Suhadolnik, LeBleu, and de MeirLeir and others in Belgium. Theoretically, this abnormality could affect energy metabolism and explain exercise intolerance. The Snell study found a correlation between exercise intolerance and an endproduct of the damaged 2-5A pathway.
Kevin Maher and others did a study of perforin, a chemical that is common in many immune system cells. They found that in CFS this chemical is reduced in NK cells and is activated in CD8 cells. In other studies, animals that were genetically engineered to have low or no levels of this kind of chemical showed a CFS-like illness. The Maher study observed reduced cytotoxicity (immune system killer cell function), activated lymphocytes in various subsets, elevated levels of immunoglobulins (IgG in particular), increased levels of immune molecules called pro-inflammatory cytokines, and reduced activity of a particular kind of immunity called delayed hypersensitivity. So this paper raises the prospect that deficiencies of perforin might help explain the abnormalities seen in CFS.
Mahurin used MRI to study CFS patients. MRI can measure activity in the brain in general. When CFS patients are given a cognitive task, they feel as if they are working very much harder than healthy people. This MRI study showed many more areas in the brain lighting up for CFS patients than for healthy controls when these tasks are given.
Studies by Gracely showed that among fibromyalgia patients, response to a high pain stimulus was much more vigorous than among healthy controls. These studies suggest that brain chemistry is altered in fibromyalgia and possibly in CFS.
There were several studies regarding possible new treatments, although none of them have yet been proven.
There is a newly released drug called Modafinil that is used for narcolepsy. Dr Rammohan tested Modafinil in patients who have MS (such patients have a substantial amount of fatigue). This trial involved about 70 patients and was randomized and placebo-controlled so that individual patients were getting either the drug or a sugar pill. By several different fatigue scales, patients on the drug showed reduced fatigue. A somewhat disturbing finding was that at double the dose the beneficial effect disappeared. On the plus side, Modafinil has few adverse side effects. This study was not yet convincing even for MS, however since there are so many parallels between MS and CFS, this research may someday prove useful.
Kristin Lambrecht et al. conducted a study of the drug etanercept, which blocks an immune system molecule called TNF-alpha. This drug is known to help with rheumatoid arthritis and is very effective for inflamed joints. In this CFS study, severe fatigue seemed to get better when the drug was applied. This trial merely involved six patients and was not randomized nor controlled. This area needs more study. Also note, the drug is expensive, about $18,000- 20,000 per year, and is not covered by many insurance companies, certainly not for CFS treatment. So this is not close to being a wonderful new treatment, but this research study is nonetheless a step forward.
Nancy Klimas et al. presented a study of an experimental immune therapy for CFS. Klimas’s study assumes that TH2 response is excessive in CFS, while TH1 is insufficiently aggressive. The treatment procedure is to first surgically remove lymph nodes from CFS patients, then take cells out of those lymph nodes and bathe those cells for two weeks in certain immune chemicals in order to shift their reaction from that of TH2 to TH1, then infuse those same cells back into the patients’ bloodstream to see whether that would change the physiology of their immune response. In a very few patients the immune response was changed as measured by two immune chemicals, and these patients began to feel better over 24 weeks. This study was not randomized nor placebo-controlled, but the procedure has worked in other immune system-mediated illnesses. If this treatment is shown to work for CFS, we should expect it to be expensive, although that could conceivably change in the future.
[Dr. Vallings is a general practitioner from Bucklands Beach, Auckland, New Zealand. Her practice is mostly CFS patients and she has seen about 2,000 patients with the illness. This is part one of her three-part report on the AACFS CFS conference held in Seattle.]
From January 26-29, 2001, I was privileged to attend the AACFS 5th International conference for Chronic Fatigue Syndrome hosted by Sudhir Gupta, the President of AACFS. It was an exciting experience to once again learn of the great wealth of research currently taking place, and to meet with those researchers and clinicians who are at the cutting edge. On the first afternoon, there was a pre-conference symposium looking at optimization of the case definition. Then followed 2 intensive days of research and clinical presentations from all over the world, coupled with a display of posters representing many disciplines. I really enjoyed the opportunity to be part of the ever popular Clinician to Clinician session, and there was also a lively forum to discuss the possibility of name-change. We were also hosted to a fine banquet at which Professor Anthony Komaroff was awarded the Perpich Memorial Award, and gave a brilliant speech recounting his experiences with CFS.
In the following report, I have tried to sort the presentations into sections according to various disciplines, following the conference format as far as possible.
The conference opened with a presentation by L Steele (Kansas) who had looked to see if the case definition for CFS was useful in describing the health problems experienced by those suffering from Gulf War illness. She concluded that although CFS is more common in Gulf War veterans than in the general population, there were 6 distinct symptom groups and only 7% fitted the case definition for CFS.
R Nisenbaum (Atlanta) discussed the course of illness among 38 of the 82 patients who were diagnosed with CFS in Wichita, Kansas between 1997 and 1999. After 12 months, 68% had transitioned to other illness states, such as non-fatigued, less CFS symptoms or medical or psychiatric exclusionary conditions. Half the patients reported that reduced fatigue was the first symptom associated with improvement, followed by improved memory and concentration, reduced joint pain and better sleep. Most effective reported treatments were: traditional medical therapy, changes in diet, vitamins, herbal remedies and exercise. There was no association between illness improvement, type of onset or illness duration.
Among a random sample of 18.675 respondents in Chicago, 32 were diagnosed as suffering from CFS. L Jason (Illinois) discussed the issue of then subtyping these individuals according to type of onset, symptoms etc. He concluded that subtype differences may account for the inconsistencies among CFS patients grouped into one category, and that subtyping may well lead to more appropriate treatment strategies.
P de Becker (Brussels) produced results of a factor analysis which determined 4 symptom groupings: general, cognitive, musculoskeletal and mood changes/psychiatric factors. The first 3 group scores fitted with both Holmes and Fukuda defined CFS patients, while the mood change/psychiatric factor score was not an important factor in determination of CFS. The musculoskeletal factor determined exercise ability.
The SF36 as a useful tool in determining outcome in patients with CFS and comparing with depression was discussed in 2 papers presented by S Schwarz (Tulsa). He concluded that admission scores on the physical component summary might be able to predict which CFS patients will worsen over time. Those who improved on the physical type scales tended to have higher mental type scores at admission and follow up. There were initial differences between CFS and depression, and CFS patients did not display the same improvement with treatment as seen in depression.
Epidemiological issues were addressed in 7 posters. R Taylor (Chicago) stressed the importance of distinctive diagnostic validity of 5 conditions: CFS, fibromyalgia, somatic depression, somatic anxiety and irritable bowel syndrome. P de Becker (Brussels) compared CFS patients fitting the Holmes and Fukuda definitions for CFS, and found that those fitting the Fukuda criteria were the less severely affected patients, which leads to an increase in clinical heterogeneity.
Factor analysis was also used by P Levine et al (washington DC) to detect subgroups in CFS and GWS. They concluded that this should be utilised in future to develop case definitions for CFS. Different pathogeneses and/or possible response to treatment may thus be identified. T Gerrity (Washington DC) suggested that Gulf War illness may be a demonstration of how fatiguing illnesses can assume different manifestations, but may still be mediated through similar neuroregulatory pathways.
J Alegre (Barcelona) had used the Fatigue Impact scale to evaluate 57 patients with CFS in Spain. High scores and the cognitive dimension parameters correlated with illness duration.
E Lindal (Reykjavik) presented the results of a mail survey to estimate the current prevalence of CFS in Iceland. The number estimated according to the Fukuda criteria was 2562. If these results were generalised to the US population, 2.5 million individuals would be apparently afflicted.
In a presentation by P Soetekouw (Nijmegen), orthostatic intolerance was not shown to be increased in CFS heart rate and plasma epinephrine were increased in CFS, suggesting an activated pathoadrenal state. Sympathoadrenergic reactivity to head-up tilt was not altered in CFS patients. A Peckerman (New Jersey) presented results of a study supporting the hypothesis of altered baroreceptor control of blood pressure in CFS. This effect of the illness may mark patients with more severe illness. A greater suppression of the baroreceptor reflex in CFS during orthostatic stress, but not during mental stress, may reflect impaired ability to maintain cardiac output under conditions of decreased preload.
J Baraniuk (Washington) studied handgrip responses to determine sympathetic nervous system dysfunction, which was found in this preliminary study to be an integral part of CFS pathology.
P Englebienne (Brussels) explained how the interaction of RnaseL ankyrin domain with ABC transporters might explain pain and many of the physiological disorders of CFS. The study suggests that the possible dysregulations in ABC transporter function find an origin in their abnormal interaction with the small fragments of RnaseL containing ankyrin repeat motifs, released from a proteolytic cleavage of pathological origin.
As an accompaniment to the work presented by Englebienne et al several posters were also displayed clarifying the work of the Belgian team. The first indicated that the 37kDa LMW RnaseL fragment is produced by proteolytic cleavage of the native 80kDa monomeric protein. Calpain has been identified as one of the proteolytic enzymes involved in the cleavage. The 37kDa fragment could retain both the 2-5a binding and catalytic activities. S Roelens’ posters (Brussels), concluded that in peripheral blood mononuclear cells (PBMC) in CFS a correlation exists between the presence of 37kDa binding RnaseL protein and a 26kDa actin fragment. Some of the actin fragments seen in CFS patients are likely to be generated by apoptotic proteases. Also the amount of native actin in the serum correlates with the amount of RnaseL in the PBMC extracts of CFS patients. A further poster showed that the activation of RnaseL in the PBMC of CFS patients upregulates apoptotic activity in these cells, which is likely to be further downregulated by the large accumulation of its proteolytic cleavage products. This suggests that accumulation of LMW RnaseL fragments in the PBMC could exert a blockade in the apoptotic cascade, impairing the elimination of already damaged cells. RnaseL and G-actin fragments were retrieved in sorted CD14+cells, which suggests that the perturbed apoptotic process may play a role in the altered immunologic functioning in CFS.
Biochemical evidence presented by S Shetzline (Brussels) indicates that the origin of the 37kDa RnaseL in PBMC extracts is more complex than previously reported as analysis revealed peptide sequences equivalent to human 80kDa RnaseL.
D Bell (Lyndonville) showed how orthostatic testing can be safely done in the office setting by recording supine pulse and BP every 5 minutes for 10 minutes, followed by standing pulse and BP every 5 minutes for 30 minutes. Results were compared with measurements of erythrocyte mass and plasma volume and a clear relationship was shown between orthostatic intolerance and circulating blood volume.
Defective vasoconstriction was found in adolescents with POTS and CFS by J Stewart (New York). During tilt, defective vasoconstriction translates into enhanced pooling of dependent limbs. This may signify a redistribution of blood to the lower extremities even while supine, accounting for tachycardia through vagal withdrawal.
There were 2 posters from Japan: K Ohashi (Tokyo) demonstrated that strenuous exercise in CFS is associated with variability in circadian activity. Y Yamamoto (Tokyo) found that head-up tilt was associated with significant differences in heart rate variability between controls and CFS patients. This can be a useful test aiding diagnosis.
W Nix (Mainz) found that there was delayed recovery of muscle force in CFS, although the actual development of fatigue was similar in patients and controls. A combination of central and peripheral factors seem to be involved. In his second poster he evaluated muscle fatigue by single fibre EMG, and abnormal findings were not shown
P de Becker (Brussels) compared exercise capacity in healthy sedentary females with that in females with CFS. There was significant decreased capacity in those with CFS, and reaching the target heart rate seemed to be the limiting factor. Autonomic disturbances may be implicated. J VanNess (Philadelphia) also looked at cardiopulmonary exercise testing in CFS. Level of functional impairment can be assessed by use of VO2 max, which was low in the population tested. There was no control group, so it is unclear whether the results indicate effects of inactivity or pathology.
The first paper in this session was presented on behalf of P Cheney (N Carolina). All chronic illnesses studied including GWS and CFS show prominent circulating plasma RNAs not observed in normal controls. Prominent RNA bands so far sequenced show homology with human genes which are noted for their tendency for gene rearrangement under severe physiologic stress. The sequences appear to be disease specific, varying by less than 1% between individuals with similar illness. Gene probes may therefore provide novel diagnostic and treatment possibilities.
C Snell (Philadelphia) concluded in his study that elevated levels of RnaseL are associated with reduced VO2max and exercise duration in those with CFS. The low tolerance for exercise maybe linked to abnormal oxidative metabolism, perhaps resulting from defective interferon responses. The results have implications for the testing of antiviral therapies in CFS, particularly those directed at the 2-5A synthetase/ribonuclease L pathway.
Assessment of the frequency of HHV6 in CFS was undertaken by the team at Columbia. D Ablashi showed that the majority of 24 patients studied from Incline Village, Nevada had HHV6 infection. HHV6 was detected in the plasma, CSF and PBMCs. The data suggests the presence of cell free infectious virus in the CSF. It was postulated that HHV6 invading the CNS may participate in the neurological manifestations of the disease. The potential for use of antiviral agents such as Foscarnet and Valciclovir was discussed, but some of the newer agents maybe more appropriate to determine whether HHV6 does play a role in CFS.
A poster also presented by Ablashi et al, showed good concordance between reactivation of HHV6 and presence of RnaseL. They could therefore be used together or separately in monitoring response to treatment. 2 patients were treated with ampligen, which inhibited HHV6 replication and upregulated the 2-5a synthetase/RnaseL pathway.
P de Becker (Brussels) presented data on 1546 CFS patients and 309 with chronic fatigue, showing that infectious agents, transfusion or hepatitis B vaccination may play an important role in the onset of CFS. Associated with these a number of stressors and consequent immunological and neuroendocrinological changes can contribute to the onset of the illness.
CFS patients with active HHV-6 infection were shown by J Brewer (Phoenix) to have activation of coagulation and are hypercoagulable. Hereditary thrombosis factors will increase the tendency. This maybe a significant factor in CFS contributing to symptoms.
C Jadin’s poster (S Africa) reflected on the importance of screening for rickettsia, chlamydia and mycoplasma in a number of diseases including CFS. This can provide valuable tools for treatment. That work was furthered also by P Bottero (Paris) who stated that these organisms may be implicated in CFS.
Low titres of antinuclear antibodies were found in 48% of those with CFS in a study of 68 patients in Barcelona by J Alegre et al. A small percentage of patients had markers of viral reactivation (EBV, CMV).
Lyme disease was addressed by M Cichon (Florida). 37 patients had been screened for Lyme disease as an exclusion in a study for CFS using ampligen. 14 of these patients had a positive test using the Lyme Urine Antigen test, which was found to be the most sensitive of all tests tried.
K Maher et al (Miami) had found in preliminary studies that the intracellular content of NK cell lytic protein, perforin, correlates with the cytolytic potential of the cell. If perforin is removed in mice, the immune abnormalities are the same as in CFS and also as in a genetic disease of childhood (FHL) in which there is a mutation in the perforin gene causing impaired cytotoxic activity. Cytolytic protein granule protein concentrations were measured in CFS in an attempt to define the mechanism underlying the reported cytotoxic effects in CFS. Results showed that intracellular perforin was reduced in NK cells and in cytotoxic T cells in CFS patients. The findings substantiate the claims of an NK associated defect in CFS and suggest a molecular basis for reduced cytotoxicity.
Auto-immunity in CFS was reviewed by E Tan on behalf of a large international multicentre study. Low titres of antinuclear antibodies had previously been found in CFS patients, but although this could be a marker for CFS, it does not mean CFS is an auto-immune disease. This study was directed at extending initial observations showing the presence of autoantibodies to a cellular protein, expressed primarily in neuronal cells (MAP2). This is one of the most abundant proteins in neurons and is a marker for neuronal health. Disparities were observed in reactivity with MAP2 in CFS from the different centres and in normal controls. This may be a reflection of the heterogeneity of CFS patients from one centre to another. This may confirm the importance of subcategorising CFS studies according to issues such as type of onset, gender, illness duration etc. The disparities in controls remain unexplained. Preliminary evidence however, shows that other proteins beside MAP2 might also be target antigens in CFS autoimunity.
K de Meirleir (Brussels) found that the presence of an increased amount of LMW RnaseL correlates with higher levels of IFN gamma, which has antiviral properties. Normal NK cell numbers and high LMW/HMW RnaseL ratio correlate with higher IL-2 levels in CFS patients compared to controls.
Immunological studies on the blood of patients with Gulf War Syndrome were undertaken by A Vojdani (California). Results indicated that as with CFS, these sick veterans are suffering from neuro-immunological disorders.
A study using mice was presented by W Sheng (Minneapolis) and supported the hypothesis that cytokine expression in the CNS is involved in neurobehavioural responses to immunologic stimuli, coupled with reduction in activity. However psychological/physical stimuli such as swim-stress did not invoke upregulation of cytokine expression despite the resulting reduced physical activity.
J Goldberg (Chicago) gave an overview of the role of genetic factors in CFS and the designs and methods that are used in genetic epidemiology and their use in CFS. One can study families looking at family history of disease and clusters of disease, or one can study fixed family clusters such as siblings, twin pairs etc. Family studies that involve DNA markers can be used to demonstrate genetic linkage to known marker loci.
A co-twin control study looking at psychiatric comorbidity in CFS was presented by R Herrell (Chicago). He found that lifetime PTSD, major depressive episode and panic disorder were more common in those with CFS than their unaffected co-twins. There is overlap in symptoms of CFS and depression (fatigue, poor cognition and sleep disorder) but this does not entirely account for the association.
Further twin studies were undertaken by N Afari (Seattle) and she had looked at the prevalence of chronic fatigue in the offspring of twins with and without CFS. She found that there was a substantial risk of having Chronic Fatigue for the offspring of both MZ and DZ twins where one twin had CFS. This is consistent with the possible familial nature of Chronic Fatigue. The offspring of the healthy member of the DZ pairs seem to be at greater risk than the offspring of the healthy member of MZ pairs. This suggests familial clustering of fatiguing illness in extended families with a member who has CF.
Comorbid clinical conditions in Chronic Fatigue using co-twin controls were undertaken by L Aaron (Seattle). She concluded that chronically fatiguing illnesses are associated with high rates of many clinical conditions. Prevalence of comorbid conditions was considerably higher in the fatigued twins than their non-fatigued co-twins. (e.g. fibromyalgia, irritable bowel syndrome, chronic pelvic pain, multiple chemical sensitivity and TMJ disorder). Regression analysis indicated that these associations could not be attributed solely to psychiatric illness.
D Lewis (Washington) used regional cerebral blood flow SPECT imaging to evaluate the relationship with CFS in monozygotic twins discordant for CFS. There was no evidence of distinctive patterns associated with CFS.
A further presentation by J Goldberg (Chicago) showed that the concordance rate for each definition of chronic fatigue is higher in MZ twins than DZ twins. This suggests that genes may play a role in the aetiology of CFS.
However a study by Sabath et al (Seattle) found that the immune systems in discordant twin pairs were dissimilar and concluded that there was not a genetic basis. When looking at aerobic capacity in MZ twins discordant for CFS, R Schoene found that while exercise capacity was reduced in the CFS affected twins, both of the pairs of twins had strikingly suboptimal performances, suggesting familial susceptibility for low aerobic capacity.
D Petersen (Nevada) found that 81 of 85 patients with CFS had deficient or absent levels of mannose-binding protein (an opsonin associated with various chronic diseases), giving credence to the theory of genetic predisposition.
R Mahurin (Seattle) opened this session by presenting research suggesting a potential means of identifying and quantifying neural substrates of task difficulty, cognitive effort and mental fatigue, using SPECT scanning. Unique features of cognitive impairment were identified, with those with CFS seeming to need to make more mental effort for cognitive tasks.
When looking for Chiari-1 malformations, D Clauw (Washington DC) did not find MRI evaluations of the cervical spine and posterior fossa differed in fibromyalgia subjects or controls.
G Moorkens (Antwerp) found there were specific neuro-endocrine differences after Hexarelin and GHRH administration between Fibromyalgia and CFS patients, suggesting different etiological mechanisms. GH, ACTH,TSH and prolactin responses were studied.
Two studies were presented by R Gracely (Washington DC). The first looked at the likelihood of a central defect in pain processing in fibromyalgia. Using MRI, activation of similar cerebral regions suggests cortical or subcortical amplification of pain in FM. A relative lack of response by the thalamus and caudate in patients is consistent with previous studies indicating reduced activity in these structures in chronic pain. The second controlled study, using ascending stimuli compared to random stimuli, suggested that expectancy effects do not account for the heightened pain sensitivity in FM.
A modified PASAT was used by G Lange et al ( NJ) to show that CFS patients, with objectively documented difficulties in auditory verbal information processing, demonstrated poorer performance during data acquisition. There was unique right hemisphere activation in the regions of the frontal gyrus, inferior parietal lobe and right post-central gyrus, as well as in the left posterior cingulate and right thalamus. These results are consistent with activations in healthy adults when task complexity is high or when performance is poor. Lange’s second poster had found that some CFS subjects had some enlargement in the body of the lateral ventricle. This maybe associated with white matter loss in the frontal and parietal lobes.
N McGregor et al (Newcastle, NSW) found that there was altered visual processing in CFS patients, and this was associated with evidence of altered connective tissue turnover and the accumulation of dietary trans-fatty acids.
B Evengard (Stockholm) concluded that there are different neurobiological profiles in CFS patients when compared with those with burnout and healthy controls. This suggests different underlying pathological processes.
As a lot of research was going on in this part of the world, it was interesting to hear an overview of the developments in CFS in these regions.
J van der Meer presented figures suggesting a CFS prevalence of 451/100,000 in the Netherlands. He told us that 13% Dutch GPs never diagnose CFS, compared to 27% in 1993. The perceived problems by GPs were need for long consultations (89%), communication difficulties (43%) and poor co-operation (31%). 78% of cases are referred to specialists and 47% of cases are not diagnosed by GPs.
Assessment is multidimensional and includes a checklist for individual strengths, SIP, Beck, actometer, neuropsych and exercise testing. These instruments can then be used in clinical trials, such as using fluoxetine, nutritional supplements and CBT. Longitudinal assessments using these tools can also add to clinical judgement. Use of computer assisted diagnosis was also discussed. There was shown to be a discrepancy of 12% between computer and clinical assessment with computer diagnosis being stricter. Physicians generally find assessment of impairment in CFS difficult.
Regarding pathogenesis, a combination of predisposing factors and heterogeneous initiating factors are thought to combine with somatic and psychological perpetuating factors to produce ongoing symptoms. No evidence has been found in the Netherlands for a role of persisting pathogens such as mycoplasma, Bornavirus, CMV, HIV or Dengue fever. Immunologically, the cytokine changes do not correlate with illness severity.
Gijs Bleijenberg then reviewed studies of 3 groups of patients using CBT, group support and natural course of illness. Fatigue and functional impairment were measured, together with outcomes such as performance, psychological wellbeing and work rehabilitation. He pointed out that focusing on symptoms caused impairment and fatigue, coupled with loss of control, and the fact that physical attributions meant that fear of fatigue following exercise impaired exercise involvement. Those participating in CBT had 16 one hour sessions over 8 months, the support group had 11 one and half hour meetings over 8 months. All patients wore an aktometer for 2 weeks. 31% of the CBT group dropped out and were found to be those with more psychological co-morbidity. Those completing CBT had a definite positive outcome, while the support group and natural course groups experienced minimal improvement. There was significant improvement (up to 50%) both clinically and in Karnofsky scores in the CBT group. The therapists involved had no prior clinical experience of CFS and 82% agreed that those with CFS were more difficult to treat than psychiatric patients. Final conclusion was that CBT was more effective than attendance at support group, but was less effective in those who were passive rather than active. A protocol for the passive patients needs to be developed. He pointed out the importance for CFS patients of initially rehabilitating towards personal activities rather than work, because of the difficulties in getting a job after prolonged illness.
A further Dutch study had looked at fatigue in CFS compared to recovered breast cancer patients. Fatigue was rated as severe in 38% of the cancer patients, but fatigue impairment was worse on all parameters in CFS.
The Belgian perspective was covered by K de Meirleir and P Englebienne (Brussels) who pointed out that they headed a specialist hospital clinic where all patients were referred and tended to be the most severe. These patients therefore had a very thorough and specialised clinical workup. SPECT scans were found to be generally abnormal, the proliferation index of T lymphocytes was diminished.
Possible triggers were considered and 60% of patients were found to have an infection at onset. 50% had two onset factors. The increased sensitivity to alcohol experienced by most patients would point to an ion channelopathy. Symptoms were factor analysed and fell into 4 main groups: general, cognitive, musculoskeletal and mood change/psychiatric.
Much of the Belgian research focused on the abnormal enzyme pathways and 88% of patients tested positive to RnaseL, (as found by Suhadolnik). The 37Kda is produced by calpain cleavage, and the whole process affects the calcium and potassium channel mechanisms. RnaseL is a likely marker for CFS, and correlates with severity. (It is negative in AIDS). The ALT and the haematocrit are adversely affected by the abnormal RnaseL ratio and when the ratio is higher the serum calcium is low, which is consistent with a channelopathy. The channelopathy will lead to low body potassium because of loss, metabolic alkalosis and hyperventilation syndrome. Symptoms relating to CVS, abnormal hormone levels and abnormal exercise response follow. There is a secondary hypomagnesia, abnormal sodium retention and changed tryptophan uptake. The latter leads to depression. The CD4/CD8 ratio correlates with VO2 max. A very complex model was proposed, the mechanism leading to a Th1/Th2 shift with viral reactivation and intracellular opportunistic infections. 68.7% patients were infected with mycoplasma in Belgian studies with a predominance of M.hominis. Mycoplasma can lead to calpain cleavage. Mycoplasma can invade all tissues such as monocytes, muscle cells etc.
Therapeutic strategies were aimed at restoration of immune competence with normalisation of the Th1/Th2 ratio coupled with elimination/decrease in the load of micro-organisms. These are 2 completely different approaches, which need to be used together, and the reason some treatments fail maybe because of a unilateral approach. Ampligen has been found to be of great benefit though is still very expensive and difficult to access in most countries. Antibiotics such as azithromycin have been found to lead to 50% clinical recovery after a long course (often 6 months of treatment completely restored very young patients). Shorter courses often lead to relapse after completion. Specialised techniques such as PCR and gene tracking for mycoplasma have led to better outcomes.
CBT has been used in Belgium with some success, but the effects seem to be temporary, and long-term studies at 4 years show a tendency to relapse in most people. 8 year follow up of patients using the above de Meirleir protocol show 92% still have not relapsed.
Filed under: Conference Reports & etc.
July 28, 2004 • 2:47 pm Comments Off
WMECFSG would like to thank Dr R. Vallings for permission to publish this report on Brainstorm.
9-12 September, 1999
Reviewed by:
Rosamund Vallings MB BS
Auckland
New Zealand
From 9-12 September, 1999, I was privileged to attend the Second World Congress on Chronic Fatigue Syndrome and related disorders. This was hosted and efficiently organised by Professor Kenny de Meirleir and his team from the Vrije Universiteit Brussels. On the first afternoon we attended a pre-conference symposium on Gulf War Illness. Then followed 2 intensive days of presentations of scientific papers coupled with posters displaying a wide range of scientific endeavour and new ideas. The conference was well attended by physicians, researchers, health workers and patients from all around the globe. There was ample opportunity for mixing and mingling at the regularly scheduled breaks, and as always this is the time for sharing of ideas and networking for future interaction. We were also treated to a relaxing social programme coupled with wonderful weather in which to enjoy Brussels at its best.
In the following report I have tried to follow the conference format, when the sessions were categorised according to various disciplines.
The conference opened with a keynote address by Neil McGregor, from Newcastle, Australia, who gave an overview of the current biochemical research in Australia, followed by a discussion of the biochemistry of chronic pain and fatigue. In their studies, no single virus has been implicated in Chronic Fatigue Syndrome (CFS) and 75% of patients, compared to 14% of controls, showed elevated RnaseL activity. The metabolic events associated with chronic pain differ from those associated with chronic fatigue. Chronic pain was associated with reductions in serum sodium, changes in urinary volume and output of amino and organic acids, increases in levels of markers of tissue damage (ALT, AST), and increase in the tyrosine/leucine ratio, representing alterations in protein turnover. Chronic fatigue was associated with alterations in urinary excretion of amino and organic acids associated with the tricarboxylic acid cycle.
Symptom expression relates to cytokine activity, urine volume and chemistry. The mechanism for chronic pain was clarified as related to catabolism (enhanced proteolysis) in muscles. We take amino acids from muscles as we fight infection and this leads to muscle protein depletion. A number of the urinary metabolites are altered in CFS, which provide evidence for proteolysis.
The urinary volume is increased in pain and fatigue states, and this can lead to reduced blood pressure and blood volume, coupled with loss of metabolites. This phenomenon is helped by added salt in the diet and the use of blood pressure raising medication. Antidepressants are found to be helpful by improving kidney function leading to reduction in urinary output, improved metabolism and reduction in fatigue.
McGregor then talked about myofascial pain, which occurs in 60-70% of CFS patients. Intensity of symptoms was found to correlate with carriage of toxin-producing coagulase negative staphylococci. This maybe a secondary contributory bacterial phenomenon. The presence of the toxin correlated positively with cytokine levels and symptom expression.
This discussion was furthered by Henry Butt, another of the Newcastle team. He discussed the association of the staphylococcal membrane-damaging toxin and chronic fatigue/pain. 90% of 73 patients reviewed were found to be positive for the membrane-damaging toxin with almost nil being found in controls. Pain severity was found to correlate with level of toxin and significant alterations in urinary metabolites. In particular, tyrosine was elevated and leucine decreased signifying altered proteolysis. Cognitive function also correlated with toxin levels. It was recommended that nose, throat and low vaginal swabs should be taken when staph infection is suspected. If pain improves with antibiotic use, this may help confirm diagnosis.
Hugh Dunstan, Newcastle, then discussed the development of laboratory-based tests in relation to essential fatty acids (EFAs) and cholesterol. He reiterated the heterogeneity of CFS and the fact that we may never therefore have a yes/no definitive test for CFS per se. His research has shown that CFS patients had significantly different profiles of fatty acids and sterols compared with controls. The most important factors in discriminating controls from CFS patients were decreased elaidic acid and increased stearic acid. CFS patients also had low levels of cholesterol, which affects cell membrane integrity and function, steroid hormone synthesis, energy metabolism and bile production. The CFS patients could be subgrouped according to their lipid profiles. (e.g. different profiles in those with acute onset compared with those with gradual onset). Some of the changes maybe due to viral reactivation or secondary infection.
The assessment of fatty acids and sterols in fasting plasma samples can indicate EFA deficits, suggest appropriate types of EFAs for supplementation, indicate potential cholesterol deficit associated anomalies, provide evidence for mitochondrial dysfunction and categorise CFS patients into biochemical subgroups. This can help to devise individually tailored management protocols.
Visual processing disablility (scotopic vision) had been researched by Tim Roberts, Newcastle. The fact that patients with visual problems reported feeling better after taking antibiotics or amino acids led to a study investigating the possibility that biochemical anomalies in CFS correlated with visual processing anomalies. Urine excretion data revealed a number of biochemical abnormalities associated with symptom expression. These patients were shown to have Scotopic Sensitivity/Ihrlen Syndrome (SSIS) and it seems likely that there are specific biochemical markers. Hydroxyproline and proline were found to be significantly elevated. The lipid profiles also help in diagnosis and there was correlation with those suffering from conditions such as dyslexia and ADD with SSIS.
Children with reading difficulties (e.g. dyslexia) can be helped by the use of Ihrlen’s filters. It is postulated that this approach maybe useful in CFS also, where there seems to be inadequate visual processing linked to dyslexia, with blurring and movement of print, and problems in the magno-cellular perceptual system. Use of coloured lenses or cellophane or coloured background to the computer screen, can have a major impact in improved reading ability and decrease in headaches. Different patients are found to need different colours. Amino acid supplementation and use of antioxidants may also be helpful. Pathogen elucidation and elimination can also be useful.
H.Kuratsune from Osaka, Japan and his team have studied acetylcarnitine (ACC) levels for some time now, and have found that the majority of patients do have depleted serum levels. There is clear correlation between acetylcarnitine levels and rating score of fatigue in CFS. Acetylcarnitine is found (in mice) to be involved in the biosynthesis of major neurotransmitters like glutamate, aspartate and GABA. Acetylcarnitine metabolism and cerebral blood flow has been found to be deficient in Brodman’s areas 9 and 24 areas of the brain associated with executive functions, such as affective and motivational behaviour and attentive and autonomic functions.
This session began with an overview by LeBleu (Montpellier, France) of the interferon-activated 2-5a/RnaseL pathway. Interferons have been characterised as mediators of a broad range of defence mechanisms particularly against viruses. Further evidence shows their involvement in immune regulation, cell growth and differentiation control.
In CFS the RnaseL is a low molecular weight variety (normal is high molecular weight). The whole pathway is upregulated. RnaseL comprises 741 amino acids.
Robert Suhadolnik from Philadelphia continued to confirm his work that the RnaseL pathway is upregulated in CFS and has continued to demonstrate the presence of a low molecular weight (LMW) form of this enzyme in peripheral blood mononuclear cells (PBMC) in CFS. 2 independent experimental methods were used to demonstrate the presence of this enzyme. Both methods demonstrated significantly statistical agreement with clinical diagnosis and showed a high degree of specificity and sensitivity. The levels of the LMW RnaseL correlated with Karnofsky scores. The presence of the LMW was independent of the duration of the CFS, and the CFS patients could be identified accurately. The drug Ampligen has been found to normalise the pattern.
K.De Meirleir also found the presence of LMW RnaseL in 680 of 705 patients studied. A more pronounced RnaseL dysfunction correlated with the 1988 definition for CFS and this may relate to the more acute viral onset stressed in that definition. But RnaseL dysfunction also correlates significantly with those fulfilling the Fukuda definition. Presence of the abnormal enzyme also correlated with increased incidence of bronchial hyperactivity. Favourable outcome after ampligen treatment is inversely correlated with the presence of LMW RnaseL.
The immunology session began with an overview of the immunological abnormalities in CFS by Nancy Klimas (Miami).
There is always a trigger factor with 60-80% cases having acute onset with viral infection (e.g. EBV,CMV, Qfever,RRV etc.). There maybe genetic predisposition. Psycho-neuro-immune mediators are important factors (e.g. stress preceding the illness is evident in 67% of patients).
The immune response is antigen driven and there is evidence of chronic immune activation, although the immune system is not wholly activated. Cytokines are the immune system’s messengers and 3 types were described: cytotoxic/antiviral, promoters of antibody production and pro-inflammatory (which mediate inflammatory responses). The latter can affect sleep, which both the brain and immune systems require to function efficiently. There are changes in cytokine expression over time depending on illness severity. TNF receptor expression increases with flares of illness, and type 2 expression is increasingly evident as illness persists.
There are also indirect effects on the immune system such as soluble mediators, which act on many tissues, and influences from the brain and endocrine system. Longterm stress will lead to immune dysfunction, such as reduced CD8 cells, decreased NK function and changes in T cells. Depression also causes changes in immune function.
CFS is a model of neuro-endocrine-immune interaction with immune activation, autonomic changes and alterations in the HPA axis. The immune system is both a cause and effect interacting with the autonomic nervous system and the HPA axis. This suggests antigen exposure. Immune therapies, which shift the cytokine pattern to type 1 expression, should be considered.
Allergy in CFS was then discussed by J Brostoff (London). 25% of the population do suffer from intolerances/allergy and the % is the same in CFS. He explained that food and inhalant sensitivity could lead to many health problems. Symptoms of intolerance include conditions such as migraine, irritable bowel, arthralgia and chronic fatigue. He recommended the value of trying elimination diets in helping establish whether or not a patient had intolerance. An interesting point was that diabetics rarely have allergies, and this may represent gene exclusion. He mentioned the effects of “exorphins” (external morphine-like substances) such as chocolate, which can have effects such as gut problems, addictive potential and psychological sequelae.
Multiple chemical sensitivity (MCS) which can be acute or lifelong was discussed. There is considerable overlap in symptoms with asthma, CFS, fibromyalgia, depression, somatisation disorder, hyperventilation syndrome. This presents problems with a case definition.
Hyperventilation syndrome occurs as a result of a patient with CFS being ill for a long time. There are many symptoms such as blurred vision, tachycardia, chest pain, pins and needles and yawning. He thinks the respiratory alkalosis leads to magnesium depletion, then muscle spasm. Noise sensitivity and vivid dreams often ensue.
Lambrecht from Ghent, Belgium presented work on the clinical, immunological and neuro-imaging correlations in those with CFS. This was a very thorough investigation incorporating a wide range of medical and immunological investigations, Karnofsky performance ratings, pulmonary and exercises function, MRI and SPECT scanning. Physicians without knowledge of the clinical history evaluated the neuroSPECTscans. 294 defects were found in 148 patients. Karnofsky scores correlated negatively with significant SPECT anomalies. Immune parameters were also positively correlated with scan results. 17 out of 30 patients had significant abnormalities on MRI, with 10 times the number of lesions than in controls. The findings illustrate the multisystem involvement and disability in CFS supporting encephalomyelitic pathogenesis.
Byron Hyde (Canada) then discussed his findings in 16 CFS patients. He too found there were persisting major immunological abnormalities and a subgroup had associated abnormal brain SPECTscans. He then looked at the effects of the drug Isoprinosine on the immune markers in this subgroup. He found some of these patients had marked improvement in symptoms, with associated improvement in cytokine parameters and NK cell numbers. Improvement did not show in the placebo group.
Nickel allergy was discussed by B.Regland (Goteborg) as a possible marker for hyper-reactivity in women with CFS. Of those who reacted adversely to an anti-staphylococcus vaccine used in treatment, 81% were found to be allergic to nickel (which was not present in the vaccine). Incidence of nickel allergy in healthy controls was 25%. This was postulated as a possible area for further research. L.Sterz (Prague) looked at the presence of hypersensitivity to dental and environmental metals in those with CFS. He suggests that metal-driven inflammation may affect the HPA axis and indirectly symptoms characterising chronic fatigue. Lymphocyte changes were shown in response to presence of mercury and nickel, and these improved in some patients when amalgam was removed. V.Stejskal (Stockholm) had also found significant numbers of metal-specific lymphocytes in the blood of patients with a CFS-like syndrome. This may be a genetic effect.
Garth Nicolson (California) discussed diagnosis and treatment of cell-invasive mycoplasmal infections in CFS and related diseases. Consideration was given as to whether these infections are causative, cofactors or opportunistic. Mycoplasma penetrates right into the cells and plays havoc with the mitochondria. This leads to many symptoms. The most reliable and highly sensitive method of detection is by forensic PCR. 50% of those suffering from Gulf War Illness (GWI) and family members with similar symptoms had evidence of mycoplasmal infections inside the leucocytes. In non-deployed healthy adults the incidence was 0 6%. M.Fermentans was the most common species found.
Successful treatment of positive patients with longterm antibiotics was reviewed. Relapse was common in early cycles of treatment, but after up to seven 6-week cycles, those who were symptom free tested negative to mycoplasma. 60% CFS/FM patients tested positive for mycoplasma compared to 6% of controls. Rheumatoid arthritic patients also tested 45% positive. It was concluded that treatment of these chronic conditions with antibiotics, oxidative therapy and nutritional supplements had potential for slow recovery. There were warnings about not using penicillin because of the increasing risk of reactions, including anaphylaxis.
Henry Butt (Newcastle) had investigated the changes in the distribution of anaerobic and aerobic bacteria, as well as the biochemical composition of faeces from patients with chronic fatigue and pain disorders. He found marked quantitative changes in both aerobic and anaerobic faecal microflora, with distributions significantly different to controls. These alterations may adversely affect the symbiotic benefits that normally occur between microbes and host. 60% CFS patients have gastrointestinal problems. The lipid composition of the stools in CFS showed significant correlation with gastrointestinal symptoms and changes in the distribution of gut flora. As a result, the clinician can evaluate gut dysfunction and devise individually tailored protocols.
It was interesting to note that less than 15% CFS patients had candida in the faeces and none had evidence of overgrowth.
A further presentation on the effects of the coagulase negative staphylococcal membrane producing toxin by Hugh Dunstan (New castle, Australia) hypothesised that an occult pathogen maybe an aetiological agent contributing to the sustenance of fatigue and pain. Alterations in urine excretion and microbiology in CFS were investigated. Patients had multiple anomalies in amino and organic acid homeostasis, and it was possible to subgroup the CFS patients according to symptoms and characteristic urinary profile. The imbalances suggested active muscle catabolism, which was directly related to pain severity. The carriage of toxin producing coagulase negative staphylococci was strongly correlated to the catabolic response and pain severity.
Rickettsial infection had been found to have a possible link with CFS by C.Jadin (Johannesburg) following on the work of P.Bottero from Paris. There is similar clinical presentation between CFS, a number of auto-immune conditions and Rickettsial disease. When strains of rickettsia have been isolated, all patients in her clinic are treated with cyclical courses of antibiotics such as tetracyclines over several months. Good results are claimed.
W.A.Nix from Germany studied a group of 69 CFS patients who had proneness towards infections. 16 were found to have elevated titres for various viruses. In all patients a single-fibre electromyography (SFEMG) study was performed to ascertain whether there was a muscle membrane defect or neuromuscular transmission defect causing fatigue. SFEMG studies did not show abnormalities in either group of patients leading to the assumption that these defects are not likely to be the cause of the muscle fatigue in CFS.
Alterations in HPAaxis function were proposed by J.Gaab (Germany) as a shared pathway linking aetiological and perpetuating processes with observed physiological changes, such as immune function and central activation. Plasma cortisol, free cortisol and ACTH responses in response to stress and exercise were measured in CFS patients and controls. There was evidence for a lower “set-point” of HPA activity. There was no reduction in glucocorticoid secretion and no evidence for reduced glucocorticoid activity, and the changes in HPA activity are therefore likely to be central.
B.Hyde (Canada) reviewed the technological investigation of ME/CFS. He stressed the difficulties that many would have in accessing these tests. 25% patients with acute onset tested positive by PCR for enteroviruses, while none did who had had gradual onset. Only 10% of his patients had a positive tilt table test. Red blood cell volume was reduced in 66% patients, meaning enormous implication for oxygen carriage. Blood volume was reduced on average to 60% of normal. He confirmed that immunological tests are expensive and difficult.
Tim Roberts and the Newcastle, NSW team had investigated erythrocyte oxidative damage in CFS. These patients had increased levels of methaemoglobin and malondiahyde as markers of oxidative stress and had increased mean erythrocyte volume compared to controls. Erythrocyte distribution risk was a primary factor differentiating controls and sub-groups of those with CFS. These parameters were associated with symptom expression and symptom indices in the patients. The data suggest that oxidative stress maybe a contributor in the pathology of a subset of CFS patients. This may indicate persistent underlying intracellular infection. Antioxidant therapy maybe therefore be useful in some CFS patients.
Pituitary function was studied by G Moorkens and his team (Antwerp). Comprehensive hormone testing was performed in 73 patients with 21 controls. Significant changes in growth hormone (GH) secretion were demonstrated during insulin tolerance testing and nocturnal GH secretion. Increase in visceral fat (measured by CT scan), a characteristic of GH deficiency, was clearly demonstrated. It is possible that this decrease in GH in CFS is related to poor sleep.
S.Bastien (California) tested for motor abnormalities associated with neuropsychologically compromised CFS patients. She used an extensive neuropsychological battery, and found most motor tests were impaired bilaterally. On the majority of motor indicators, the dominant hand performance was worse than the non-dominant. Male results were slightly different to the females. The results support the patient complaints of clumsiness, dropping things, weakness and slowed motor co-ordination.
Fluctuations in fatigue were described as a result of a French fatigue questionnaire by J.Cabane (Paris). Among the 10 patients, none had permanent fatigue and all had more than one period of fatigue per 24 hours. Various rhythms of fatigue were noted such as monthly, weekly and daily.
Memory impairment was examined by John de Luca (New Jersey) to see whether there is deficient learning of information in CFS as opposed to deficit in retrieval from long-term storage. A well controlled study was described. The results implied that the primary problem in CFS results from deficient acquisition as the patients required significantly more trials to learn a word list than did healthy controls, but there was also some deficient retrieval from longterm storage.
J.Hardt (Mainz, Germany) reported on the work undertaken in 3 countries to compare the quality of life of CFS patients. Remarkable similarity in self-rated functional status suggests homogeneity in CFS patients in USA, Germany and UK.
Byron Hyde (Canada) reported on 4 patients who fell ill with CFS and 4 who fell ill with MS immediately after recombinant Hepatitis B immunisation. The onset in the 8 patients was identical, but the CFS group were distinguishable, as SPECTscan changes were evident with normal MRIs, while demyelinating lesions were evident in the MS patients. The question was raised as to whether the effects after immunisation were coincidental or causal. As a result of similar worries in France this type of vaccine for children has been withdrawn. However it was pointed out that we should not forget the enormous and important benefits in preventative immunisation programmes.
Altered perception of muscle force in patients with CFS was discussed by W.Nix (Germany). CFS patients perceived that it was more difficult to generate a given force output than normals, and although the recovery phase was slower in the CFS patients, they could in fact perform as well as the controls. Its seems therefore that the fatigue could be perceptual and the possibility was raised that mental fatigue sets in earlier than the physical fatigue.
A significant degree of functional impairment was demonstrated in CFS patients surveyed by N.Posner and his team in Queensland. They used the SF36 and found particularly that these patients had significant physical role limitation. 8 dimensions were assessed and the means for each were markedly lower than the population norms. The least differences were in the mental health and emotional role limitation dimensions. Results were dissimilar from most other disease profiles, particularly depression, and indicate a very significant degree of functional impairment. Support needs should thus be recognised
K.Rowe (Melbourne) looked at whether the symptom complex of adult CFS occurs in adolescents. She studied 189 young people with defined onset of fatigue with a symptom complex lasting at least 6 months. 85% of patients had an illness following an acute viral illness. Factor analysis was used with the data from the clinical group. Symptoms reported were consistent across all subjects, and while the symptoms in CFS were similar to adults, prolonged fatigue after exercise, headache, concentration difficulties, disturbed sleep, abdominal pain and myalgia were particularly evident. Somatization disorder was not a likely alternative because of low response frequencies of such symptoms.
2 papers on exercise capacity in CFS were then presented. P.deBecker (Brussels) et al found that CFS patients were limited in their capacity to perform physical activities Females were on average more impaired than males. Exercise parameters were generally down with a mean working capacity of approximately 55% of normal. C. Sargent (Adelaide, SA) found that CFS patients were not deconditioned and a graded exercise training programme would seem unwarranted in treatment. These patients had normal exercise capacity with abnormal lactic acid accumulation demonstrated from the beginning of the exercise.
Treatment of rickettsial and chlamydial infections with macrolides and/or cyclines was discussed by P.Bottero (Paris) Symptoms may be accentuated initially due to release of bacterial toxins, but this can be combatted by the use of anti-inflammatory drugs. The drugs are used cyclically and may be needed for one to two years to obtain positive outcome. Overall results were not discussed.
Treatment with the drug Isoprinosine (an immune modulator with anti-viral properties) was outlined by B.Hyde (Canada), who described this drug as having been available for 30 years without encountering any serious side effects. Patients studied were widely and thoroughly investigated, and a group of 16 CFS patients with abnormal SPECTscans was treated using placebo control over a 7 month period. 7 patients improved on the drug, 7 remained unchanged and 2 deteriorated when on placebo, with improvement once the drug was reinstated. Improvements in general health and energy were modest but significant. All those who improved were happy to continue. Thinking and memory improved, ataxia decreased, headaches decreased, there was less clumsiness and better motor function. In particular, ability to attend social functions increased. Only one patient experienced side effects, which were bad headaches.
N.Klimas (Miami) discussed further her work showing alteration of type1/type2 cytokine patterns following adoptive immunotherapy using expanded lymph node cells. 13 patients with strict inclusion criteria were studied. Lymph nodes were removed and cells were then cultured for 10-12 days and reinfused into the donor who was monitored for safety and possible clinical benefit. No adverse events were recorded. 2 patients had unsuitable fibrotic lymph nodes, so were not included. For the remaining 11 who underwent successful expansion and reinfusion, there were favourable clinical and immunological results. It is hoped that further trials will follow.
Three studies regarding the use of the drug Ampligen were then reported. Ampligen is a biological response modifier with antiviral and immunomodulatory effects. D.Strayer (USA) had compared twice or thrice weekly infusions in order to optimize the dosing schedule. 111 patients were studied. Activity and safety of the 2 dosing schedules were compared and it was found that thrice weekly dosing offers no advantage over a twice weekly schedule. There were slightly more adverse events in the thrice weekly group, mainly myalgia and flu-like symptoms. A pharmaco-economic analysis intervention in CFS was presented by W.Carter (USA) looking at the savings on concommitant medications and hospitalisation in the treated and untreated groups. Although the cost of the drug is extremely high, considerable savings were shown to be made in these areas, which it seems could have some thrust in convincing government agencies of the potential of this drug, particularly more so if patients could eventually return to the workforce.
Finally, K de Meirleir presented his work on the Ampligen study in Belgium. 44 severely affected patients under 60 had been given the drug for 24 weeks and compared to 16 untreated controls. Infusions were given twice weekly starting with 200mg and increasing to 400mg. There was significant improvement in bicycle-exercise testing, increased Karnofsky scores, reduction in cognitive impairment, alleviation of many of the CFS symptoms and improved general health perception, significant improvement in day to day function and no serious adverse events.
A wide variety of posters were displayed and the following represents a brief overview of some of the important findings.
P.de Becker (Brussels) looked at mode of disease onset in CFS. 74% patients had acute onset with progressive disease in 26%. Infectious agents seem to play an important role in the onset of CFS with other factors such as immune dysregulation involved in the perpetuation of the illness. He also did a 6 month follow up in CFS patients. He found that health stayed unchanged or deteriorated measured by several parameters. Especially, physical capacity seemed to get worse over time. Only a small number of patients were followed over this relatively short period of time. 1248 patients were studied in a further poster by de Becker, and in almost all patients all symptoms of the Holmes criteria occurred. Other symptoms noted were: dyspnoea, lightheadedness, gastro-intestinal complaints, cold extremities, decreased libido and disequalibrium. They found the Fukuda definition less stringent and therefore less suitable for scientific homogeneity.
E.Fitzgibbon (Galway, Ireland) had used the SF36 in a postal survey of 123 CFS patients. There was 77% response rate. With a mean duration of illness of 5 years, 66% were improving, 29% were static and the remainder were worse. 26% described themselves as almost back to normal with 60% back to fulltime work or study. The females had worse general health and reported more symptoms. Quality of life was lower in all domains measured by the SF36 than norms, and the overall results were unique compared to data from other disease groups.
In the UK the diagnosis of CFS seems better accepted than Multiple Chemical Sensitivity as pointed out by D.Jones. 78 patients had completed questionnaires demonstrating the difficulties in diagnosis and the complexity of this condition. Many possible causes were cited. She had also followed up 45 patients who attributed their CFS-like illness to use of cotrimoxazole.
Midlife and elderly women’s vulnerability to CFS was discussed by M.van Moffaert (Ghent, Belgium). It seems many underlying health disorders and sociological factors increase the vulnerability to both CFS and multisomatoform disorders.
Prevalence of bronchial hyper-responsiveness in CFS was observed by K.Bervoets (Brussels). A high incidence was observed irrespective of smoking habits. This finding cannot be explained by the expiratory muscle effort involved in the histamine provocation procedure, as there was no significant difference between baseline spirometry and expiratory muscle strength between CFS patients and controls. E.Brouns furthered this work by looking to see if there was correlation between cellular immunity and bronchial hyper-reactivity in CFS. These patients were significantly found to have an increased number of activated T-cells and a decreased number of cytotoxic T-cells.
RnaseL testing was done in 136 German patients by L.Habets. RnaseL dysfunction was found in most patients with a correlation between the RnaseL/LMW RnaseL ratio and disease symptoms. M.Reynders (Brussels) found that the large amount of LMW RnaseL correlates with higher levels of IFN gamma, which has antiviral properties. Normal NK cell numbers with high LMW/HMW ratio correlate with high IL-12 levels in CFS patients compared with controls. IL-12 has been shown to be a potent inducer of IFN gamma secretion by both resting and activated T and NK cells in humans.
D.Racciati (Italy) et al observed an alteration in the antioxidative enzyme activities of skeletal muscle, and alterations of fatty acid composition and fluidity of membrane in muscles in CFS and FM patients. No similar abnormalities were found in controls. The oxidative muscle damage could represent the consequence of an impaired oxidative/antioxidative system and could possible correlate with the increased muscle fatiguability in CFS.
4 case reports by A.D.Hock (Germany) brought up the possibility that Vitamin D and parathormone disturbance should not be overlooked as a possible cause of chronic fatigue. The symptoms are very similar and this is a treatable disorder.
S.Meghan (Boston) as leader of a group of female health care workers with CFS stressed the importance of considering that as this illness seemed to be “predominantly female” we should not overlook the impact of the endocrine system as a likely factor in potentiating CFS.
Symptom patterns in adolescents with CFS were again addressed by K.Rowe (Melbourne). 189 young people were studied. 3 subgroups were identified according to severity. The more severe group had greater fatigue and pain, the moderately severe group having more neurocognitive symptoms and the least severe having more headaches, nausea and abdominal pain. Investigation of these subgroups may assist with management.
The pregnancy experiences of women with CFS were explored by R.Vallings (Auckland, NZ). Most women found the experiences positive, but the importance of family and partner support was emphasised together with an understanding of CFS by the obstetric personnel involved.
Data were collected by P. de Becker and de Meirleir (Brussels) on 1248 patients attending a clinic complaining of chronic fatigue. The patients were subgrouped after thorough review according to whether they had CFS or chronic fatigue from other disease causes. Frequency and severity of symptoms were more marked in the CFS group. The physical capacity of the CFS patients was lower and they seemed to be more debilitated. In another paper they also found that 4.5% of a large cohort of patients reported that their illness came on following surgery with an accompanying transfusion. None had developed Hepatitis C or other possible transfusion-transmitted infection. The findings do point to a possible transmissable cause in this subset of CFS patients. They therefore advise CFS patients not to offer to be blood donors. Blood transfusions also should be given when strictly necessary. While looking at possible opportunistic infections, they concluded that mycoplasmas might be partially responsible for some of the signs and symptoms in CFS. They also seem to be implicated in the T-cell activation observed in these patients.
CFS patients suffer significantly from psychomotor dysfunction, which may contribute to the global disability in the syndrome. (L.Lambrecht, Ghent). Rehabilitation methods including biofeedback and progressive aerobic training and restoring psychomotor abilities may constitute an important part of management. Low prevalence of autonomic dysfunction was found in this group of patients. The same team had evaluated neuropsychological impairment using numerous different tests and found that the Purdue pegboard turned out to be the most affected test. Visual memory span was affected and 20% of the patients were depressed according to the Beck depression inventory. When they reviewed SPECTscans in CFS patients, 189 aberrations were found in 65 patients.
O.Zachrisson (Sweden) found a high prevalence of irritable bowel syndrome in CFS and FM patients (61%) and a further 19% had other GI symptoms. A common pathogenic mechanism such as disturbed microflora in the gut was suggested.
L.Barker (Essex UK) described an 8 week group programme for CFS patients was followed up by questionnaire/audit, and results demonstrated that 71% patients improved, with a number returning to work or college. It is hoped therefore to develop outpatient services to provide a comprehensive management approach to the illness.
P.Bottero (Paris) demonstrated the immunology of Rickettsial diseases (small intracellular gram-negative bacteria). It seems that rickettsiae penetrate and persist in the macrophages and diminish their function. Accompanying immunological changes also occur.
4 papers on Gulf War Illness (GWI) were presented as part of the opening symposium.
Peckerman and Natelson (Orange USA) presented figures to familiarise us with the situation in the USA. 16.8% of returning veterans surveyed had medical problems. The rate of Chronic Fatigue in this group was 5.2% compared to 1.2% of veterans in non-active service. Of those diagnosed as suffering from GWI 50% fitted the criteria for a diagnosis of CFS. It was hypothesised that those suffering from GWI have poor control of cardiovascular stress. Cardiovascular regulation was studied using various approaches. BP tended to fall during speech and mental arithmetic tests with no difference in pressor tests. During the speech test the peripheral resistance did not budge as it should. 3 possible issues were raised: Is this: (1) related to the cause of fatigue, (2) a marker of illness or (3) a premorbid condition? The greatest physiological consequences, impacting central and peripheral control systems, occurred in veterans who sustained exposure to both chemical and severe psychological war stresses.
Using factor analysis, Paul Levene (Washington) also concluded that the identification of a cluster of neurologic symptoms in a large sample (7000) of deployed Gulf War vets that could not be found in non-deployed vets supports the possibility that environmental factors could be responsible for some of the complaints of Gulf War veterans.
M.Hooper (UK) described the Gulf War as the most toxic war in all military history. Up to 17 vaccines were given, many disinfectants were used (e.g. in insect control), many chemical warfare agents were in the area, “uranium” weapons were used creating toxic dust, biological weaponry was in the area (e.g. brucella, smallpox, viruses) and many other chemical agents (smoke, oilfires) were prevalent. Birth defects have now been found to be a major factor in Iraqi veterans’ families. Risks of leukaemia, other cancers, neurotoxic effects and possible effects on sperm are also becoming evident.
G.Nicolson pointed out that there is as yet no case definition for GWI, but the signs and symptoms loosely fit the CFS definition. Using Forensic PCR Hybridization it was found that 45% GWI patients showed evidence of mycoplasmal infections in the leucocytes but not in the plasma or serum. When comparing CFS patients, 70% of them were found positive for mycoplasma. A variety of mycoplasma species were found. These infections could be causative, cofactors or opportunistic. These infections maybe a major source of morbidity in these related illnesses. There is some evidence of possible transmission to family members. Possible other transmittable bacterial and viral infections maybe involved.
Treatment with appropriate antibiotics and nutritional support can result in improvement in these chronic conditions, though not in every case. It is possible that GWI is to a large degree due to multiple exposure to chemical, radiological and biological agents that can cause immune depression, multiple infections, and multifactorial illnesses, which maybe treatable.
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