Report from Biomedical Research Conferernce

Discussion in 'Fibromyalgia Main Forum' started by Bluebottle, Jun 24, 2008.

  1. Bluebottle

    Bluebottle New Member

    Cambridge, England May 2008

    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

    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:



    Isoprinosine, thalidomide, antiTNFa, monoclonal

    Autologous lymphocyte study.


    Antivirals such as foscanet, valganciclovir.


    Florinef (failed when used alone).

    Erythropoietin (very modest benefit).


    Beta-blockers to regulate the pump.

    HPA drugs (not particularly useful).


    Sleep routine.


    Sodium oxybate (must have sleep study to eliminate


    Melatonin (mixed results).

    Cell metabolism

    CNS directed medication


    CoQ10. alipoic acid, NADH etc


    Short 5 minute spells of upright exercise, followed by
    5 minutes of flat flexibility work can be more

    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

    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

    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

    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

    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

    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

    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

    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

    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:


    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.
  2. marti_zavala

    marti_zavala Member

    Thanks for posting this. I have pasted it into a word document to read when I am not fogged.

  3. Lichu3

    Lichu3 New Member

    "75% improved with valganciclovir."

    From the Twin Studies in Sweden. Is this just a quote from the initial Stanford studies or something else? The way it is embedded in the text suggests something else. Hope to hear more from Sweden.

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