Cambridge, England May 2008 http://www.anzmes.org.nz/medical_information.htm A review of the clinical aspects of ME/CFS by Dr Rose Vallings The first presentation was given by Professor 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 sub grouping and 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 and 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 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 over activation. 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, antiTNFa, 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. alipoic 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. Intracellular immune dysfunction in ME/CFS. Dr Jo Nijs (Brussels) gave an overview of intracellular immune dysfunction in ME/CFS. He described dysregulation of intracellular immunity and up regulation 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. TNFa 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. The development of clinical services for those with ME/CFS. Dr Gregor Purdie (Scotland) as a GP advisor to the UK 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 Patient-centred research and clinical aspects. 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. Treatments targeting the methylation cycle 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 benefited. 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. The care pathways adopted in clinical practice 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. Clinical studies focusing on autonomic issues 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. A centre of excellence 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,USA). This exciting development is to be a centre of excellence comprising 80,000 sq ft at a cost of $US 78 million. 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. Current research taking place in Nevada Dr Dan Petersen then gave an overview of the current research taking place in Nevada. He began by stating 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 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. A review of molecular studies in ME/CFS 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 =96 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 sub typing should be possible. The Swedish Twin registry-- looking for a biomarker Professor Birgitta Evengard presented her team's 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 and 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 (ERa and ER=DF) receptors are implicated in several diseases. There was reduced expression of ER=DF 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 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 has 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.