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AUTUMN EMERGE Powered By Docstoc
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                               Medical Pages
                                        by Dr Nicole Phillips

      Report on International Science Symposium on
   Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome,
3-4 December 2010, Faculty of Health Sciences and Medicine
               Bond University, Queensland.
Organising Committee
Christine Hunter, Alison Hunter Memorial foundations Dr Donald Staines, Public Health
Physician Bond University, Dr Sonya Marshall-Gradisnik, Associate Professor Biochemistry,
Bond University, Professor Mieke Van Driel, Professor General Practice Bond University.
This was an intellectually stimulating and challenging meeting comprising a selected group of
international CFS researchers and clinicians. There were some interesting research papers
presented predominantly on the first day, but it was the brilliant level of group discussion on
the second day which was so exciting as the group worked together to create a press

                                       Presenter: Nancy Klimas
  (Mary Ann Fletcher PhD and Gordon Broderick PhD University of Miami and Miami VA
                       Medical Centre and University of Alberta)
CFS continues to be studied using a traditional piece by piece approach focusing on the
failure of individual neuroendocrine and immune components. Nancy’s group is pursuing the
hypothesis that CFS results not only from component failure but perhaps more importantly
from a significant deterioration of regulatory function linking these components. They are
testing regulatory fitness by using an exercise challenge to stimulate stress response and its
modulation of the nervous, endocrine and immune systems.
The objectives of their studies are to improve the outstanding of CFS pathogenesis in three
       i by using broad-scale molecular profiling to create a comprehensive assessment of
       status in several of the body’s regulatory systems

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       ii by using information theory to integrate this disparate data into a single
       interpretable map describing the interactions between these physiological systems
       iii by using elements of network theory to study the structure of these signalling
       networks and isolate alterations in the ‘wiring’ that might be specific to CFS.
Embedded in these maps they will have captured the dynamic response of the overarching
homeostatic control to exercise stress. Preliminary data was presented looking at gene
expression in response to an exercise challenge, and a discussion of the potential to use this
sort of approach to use computer modelling of virtual clinical trails, modelling treatment
courses designed that exploit the new understanding of homeostasis in order to redirect the
system as a whole to normal resting state and a normal pattern of response pattern of
response to activity.
Three matched groups were studied, Gulf war Illness, CFS and controls. The exercise
challenge was 8 minutes on an exercycle measuring VO2 max. In GWI and CFS, the
inflammatory + immune cascade led to many symptoms hours later. The study confirms
graded exercise is not good for CFS patients who must stop exercise well short of aerobic

                        V. Hugh Perry, School of Biological Sciences,
                       University of Southampton, Southampton, UK.
The symptoms of sickness involve a spectrum of metabolic and behavioural changes
including fever, fatigue, lethargy and depression. Sickness behaviours are part of our normal
homeostatic response to an infection and play an important part in fighting the infection and
subsequent recovery.
Studies in experimental models show that there are signalling pathways from the site of
inflammation to the brain that involve both neural and humoral pathways. The evidence
shows that a number of different cytokines typically associated with infection and
inflammation in the peripheral immune system are also synthesised in the brain and play a
role in the generation of sickness behaviours. Imaging studies in man have shown that
systematic inflammation is associated with activity in particular brain regions.
However, recent studies in both animal models and in humans with neurodegenerative
disease show that systematic inflammation and common infections may give rise to
exaggerated symptoms of sickness behaviour and may also lead to acceleration of disease
progression. It thus appears that a normal homeostatic mechanism can become maladaptive
in the aged or diseased brain.
The focus of current research is to understand how the innate immune cells of the brain are
involved in sickness behaviours in the healthy and diseased brain. These studies have
possible implications for understanding the symptomatology CFS/ME and suggest new
avenues for research.

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                                   Presenter: M.A Fletcher.
            (Nancy G. Klimas University of Miami Miller School of Medicine and
                    Miami VA Health Care Center Miami, Florida USA)
In CFS there is:
   1) Reduced function of natural killer (NKC),
   2) Inflammation,
   3) Altered cytokine,
   4) Chronic lymphocyte activation and
   5) Abnormalities in stress responses in CFS.
The goal of their recent research is to discover biomarkers with sufficient sensitivity and
specificity to distinguish CFS cases from age-matched healthy controls. Their studies
examined the biomarker potential of plasma cytokines, NK cell function, soluble and cell
bound dipeptidyl peptidase IV (also known as CD26), and neuropeptide Y (NPY).
10 of 16 cytokines, NKCC, dipeptidyl peptidase /CD26 and NPY were identified as potential
biomarkers for CFS through their demonstrated accuracy in discriminating CFS patients from
healthy controls. Interestingly, NPY was 80% sensitive in CFS (better than PSA to diagnose
prostate cancer). NPY also correlates with disease severity.

                                  Presenter: DG O’Donovan
   (T Harrower, S Cader, L J Findley, C Shepherd, A Chaunhuri, Addenbrookes Hospital
 Cambridge UK, Queen’s Hospital Romford Essex UK, Royal Devon & Exeter Hospitals UK,
                    Honorary Medical Advisor to ME Association UK)
Donovan reported on the post mortem pathology of four cases of CFS diagnoses by
The causes of death were all unnatural and included: suicidal overdose, renal failure due to
lack of food and water, assisted suicide and probable poisoning.
One case showed a vast excess of corpora amylacea in spinal cord and brain of unknown
significance but Polyglucosan Body Disease was not supported by clinicopathological review.
No ganglionitis was identified.
One case showed a marked dorsal root ganglionitis and two other cases showed mild excess
of lymphocytes with nodules of nageotte in the dorsal root ganglia.
This raises the hypothesis that dysfunction of the sensory and probably also the autonomic
nervous system may lead to abnormal neural activity eg hyperalgesia and allodynia rather
than anaesthesia and many explain some of the symptoms of CFS/ME such as pain,
hypotension, hyperacusis and photophobia.

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The differential diagnosis of ganglionitis should be investigated in CFS/ME patients hence
Varicella Zoster, Lyme disease, HIV, Sjogren’s disease, paraneoplastic sensory
ganglionopathy should be excluded by appropriate history and tests.
A specific CFS/ME brain and tissue bank in the UK was proposed.

                                    Presenter: D. Peterson
(Konstance Knox, PhD; and Donald Carrigan, PhD. Sierra Internal Medicine; Incline Village,
           Nevada; Wisconsin Viral Research Group; Milwaukee, Wisconsin.)
The investigations described involved the study of a population of patients suffering
prolonged fatigue with systemic signs and symptoms consistent with an active ongoing
infection. This infective process is believed to involve active disseminated infection with one
or more leukotrophic herpesviruses.
The long range goal of these studies is to prevent the misdiagnosis of their illness as
idiopathic Chronic Fatigue Syndrome (CFS) which would justify new strategies for effective
treatments such as antiviral drug intervention.
Virological data to date has demonstrated the existence of three distinct, but overlapping
patient populations. Methods used for the detection of active human herpesvirus six (HHV-
6) and human cytomegalovirus (HCMV) were viral isolation from peripheral blood leukocytes
(PBL) using human diploid fibroblasts as the viral target and detection of viral DNA in serum
or plasma samples by nested polymerase chain reaction (PCR). Active Epstein Barr virus
(EBV) infections were detected by means of an approved serologic assay targeting the viral
EBNA1 protein. Active HHV-6 infections were detected in 28% (54/194) of the patients,
active HCMV infections were found in 29% (71/249), and active EBV infections were present
in 51% (79/153) of the patients. Interestingly, dual positivity for active HHV-6 and active
HCMV infections was significantly observed. Active EBV infections did not significantly
correlate with HHV-6 or HCMV infections. However, active EBV infections significantly
correlated with the presence of autoantibodies in the patients’ plasmas with antibodies
directed at thyroid peroxidise (TPO) and parietal cells being the most common. EBV
infections are well known to be associated with autoimmune disease such as rheumatoid
arthritis and systematic lupus erythematosus.
These studies have identified a discrete subpopulation of patients with chronic fatiguing
illness whose disease is intimately associated with active infection with one or more
leukotrophic herpes viruses. Such patients are attractive candidates for new and novel
treatment strategies such as antiviral drug interventions combined with careful viral

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                       Presenters: E Brenu and S. Marshall – Gradisnik
(Donald Staines, Mieke van Driel. Faculty of Health Science and Medicine, Bond University
 Australia, Population Health and Neuroimmunology Unit, Faculty of Health Sciences and
  Medicine, Bond University, Australia, Gold Coast Population Health Unit, Queensland
                                    Health, Australia)
ME/CFS has been shown to have an immunological component where cells especially
Natural Killer (NK) cells have been shown to be compromised. In this project the main focus
was to determine the cellular activity of cells in both the adaptive and innate immune
system to determine the degree of compromise to these cells in particular their cellular
functions. The findings from this study may assist in developing potential biomarkers for the
disease. After experimental and statistical assessment between ME/CFS participants (n=98)
and healthy control subjects (n=68) cytotoxic activity of NK cells and CD8+T cells was
significantly reduced.
Additionally, they have previously shown that NK phenotype in particular CD56 bright NK
cells are significantly reduced in the ME/CFS population and again this was significantly
lower in this larger cohort of ME/CFS patients compared to the healthy control subjects.
They found significant elevation in IL-10, IFN-Ɣ and TNF-α. They also assessed regulatory T
cells a subset of CD4+T cells and determined that FOXP3 expression in these cells were
heightened in ME/CFS group compared to the healthy control subjects. Vasoactive intestinal
peptide receptors were also investigated and these were significantly higher in their
expression in the ME/CFS population compared to the healthy control subjects.

                                  Presenter: K. de Meirlier
  (Marc Frémont, Kristin Metzger & Chris Roelant, Vrije Univesititeit, Brussels, Belgium)
Background: Chronic activation of the immune system is present in progressive HIV infection
and is a better predictor of disease outcome than plasma viral load. Several studies suggest
that XMRV is involved in the pathophysiology of CFS/ME. The hypothesis was that the
systemic immune activation in XMRV positive CFS patient is similar to the one observed in
Patients and methods: Sixteen CFS patients positive for XMRV were studied with healthy
controls. Complete immunophenotyping was performed on venous blood and also elastase
activity, C4a, IgG3, cytokines, sCD14, perforin were measured. Stool IgA was also performed
Results: The number of CD3+ and CD57+ lymphocytes was significantly lower compared to
the reference values. C4a and elastase activity were significantly higher in the XMRV positive
CFS population.

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Soluble CD14 (which codes for LPS in plasma) was significantly higher as compared to the
reference population. The cytokine panel showed increased IL-10, MCP-1, MIP-1 beta an IL-8
serum levels. Other lymphocyte subsets showed no difference from the reference in the
XMRV positive patients. Stool IgA and IgG3 were statistically lower in the XMRV positive
Conclusion: The results of this study show that XMRV positive patients have lymphocyte
numbers and CD57+ lymphocytes below normal as is observed in HIV.
XMRV positive CFS patients have an activated innate immune system (elastase activity and
C4a are increased) which could be related to microbial translocation as their sCD14 is
significantly higher than expected; sCD14 strongly correlates with plasma LPS.
Low stool IgA also indicated dysfunctional muscosa-associated lymphomal tissue (MALT) in
XMRV positive CFS patients. Furthermore their IgG3 serum levels are lower than in the
Serum levels of the cytokines IL-8, IL-10, MCP-1 and MIP-1 beta are increased in the patients
and might constitute a biological signature for the viral infection.
These observations provide evidence for microbial translocation being part of the
pathophysiology of XMRV positive CFS patients.

                                   Presenter: R. Kwiatek
(Leighton Barnden, Benjamin Crouch, Richard Burnet, Anacleto Mernone, Steve Chryssidis,
Garry Scroop, Peter Del Fante, The Queen Elizabeth Hospital, South Australia, University of
       South Adelaide, Adelaide Western General Practice Network, South Australia)
Aim: To explore brain involvement in Chronic Fatigue Syndrome (CFS) using whole-brain
optimised voxel-based volumetry and novel quantification of T1-weighted and T2-weighted
signal levels in structural magnetic resonance imaging (MRI).
Methods: Twenty-five CFS (Canadian defined) and 25 normal controls (NC) had gradient-
echo and spinecho brain MRI, and clinical evaluation including a score based on the 10 most
common symptoms, Bell Score, HADSA anxiety and depression, and hemodynamic
parameters from 24 hour blood pressure monitoring.
Results: Seated pulse pressure (PP) and seated and asleep heart rate (HR) were increased in
CFS versus NC. A strong correlation between total brainstem grey matter volume and seated
PP was also detected in CFS.
Conclusions: Brainstem and particularly midbrain involvement may have primacy in CFS,
affecting multiple feedback loops, including autonomic and cortical, disrupting homeostasis.
WM volume changes appear to involve the glial compartment. Brainstem GM changes
suggest failure of cerebrovascular autoregulation, potentially mediated by astrocytes.
Astrocyte dysfunction therefore maybe central to CFS pathogenesis.

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             Barrie P Marmion AO, E/member Hanson Medical Research Institute
        The post Q fever fatigue syndrome (QFS) – inappropriate, delayed onset, severe
         fatigue: joint pain: muscle pain and fasciculation; constant headache: profuse night
         sweats: photophobia: ethanol intolerance: disturbed cerebral function (interrupted
         sleep patterns, poor short term memory, irrational anger): loss libido.
        It follows 5 to 15% of overt acute primary Q fever but rarely subclinical infection.
         Usually it is continuous from the initial infection but may be episodic on re-exposure
         to the coxiella in environment or (briefly) to inadvertent Q fever vaccination.
        QFS was first recognised in the mid 1990’s in Australia and Birmingham UK. It has
         now been reported in Canada Japan USA and Croatia. It is an emerging feature of the
         current large goat- associated Q fever in Holland.
        Their working paradigm for QFS:
         Overt Q Fever + immune-genetic predisposition
                     Defective antigen clearance
                     Persistent heighted        cell-mediated    immunity    with    cytokine
                     Cytokine-modulated somatic gene expression
                     QFS.

 Warren P Tate, Department of Biochemistry, University of Otago, Dunedin, New Zealand
Dr Tate’s group have just initiated a study to develop tools that can accurately detect
molecular changes within cells in response to viral double stranded RNA (dsRNA), relevant to
ME/CFS. The long term goal of the research is to develop a specific diagnostic marker set for
the syndrome.

       Doina Ganea, PhD, Temple University School of Medicine, Philadelphia, 19140 PA
Vasoactive intestinal peptide (VIP), a well known immunoregulatory neuropeptide, affects
both innate and adaptive immunity, and acts as a major anti-inflammatory factor in animal
models of autoimmune diseases. VIP down-regulates the innate immune response by
inhibiting the release of proinflammatory cytokines, chemokines, and nitric oxide by
activated macrophages, microglia, and dentritic cells. VIP affects the adaptive immune

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response by reducing the costimulatory capacity of antigen-presenting cells, and by
preferentially inducing Th2-type responses.
Dr Ganea discussed the potential use of exogenous VIP in inflammatory and autoimmune
diseases. The main problem is its instability, therefore leads to a huge dose with side effects.
This problem has been bypassed by using VIP in vitro in animals to get tolerogenic dentritic

                                     Presenter: D. Staines
Sonya Marshall-Gradisnik, Ekua Brenu and Mieke Van Driel, Gold Coast Public Health Unit,
                                   Bond University
Unexplained severe fatigue-related disorders such as Myalgic Encephalomyelitis/Chronic
Fatigue Syndrome (ME/CFS) may be associated with autoimmunity affecting the function of
vasoactive neuropeptides (VNs) e.g vasoactive intestinal peptide (VIP) and pituitary
adenylate cyclise activating peptide (PACAP). Perturbations of adenylate cyclise (AC)
signalling and cAMP function possibly involving ATP toxicity and purinergic signalling may be
features of VN autoimmunity. Disruption to the blood brain barrier (BBB) and blood spinal
barrier (BSB) may also occur. Other complex metabolic perturbations affecting glucose
metabolism, purinergic signalling, glial/neuronal function, gaseous and conventional
neurotransmitters and system functions e.g. CNS and cardiac function (among others) may
occur under this paradigm. If the proposed VN autoimmunity hypothesis is true then a
number of treatment options may be plausible.

                                  Day 1: Discussion
There was discussion around the following topics:
Disease definition, diagnosis, biomechanics, interventions and promoting networks
Disease definitions
It was discussed that Dr Caruthers is leading a team to update the Canadian Clinical Criteria.
Dr Klimas stated that we must not close sight of subgroups. The Fukuda criteria do not
require exercise-induced relapse and with just 4/8 criteria required one could misdiagnose
CFS as depression.
Ellie Stein from Canada suggested we should define the disease via its biomechanisms,
whereas Hugh Perry, U.K. said this would be “dangerous”. Dan Peterson said we should have
the same disease definition around the world.
Ros Vallings, NZ said that of 6000 patients followed up, 1/3 had a different diagnosis over
time, so we do need biomechanisms. eg MS and Sjogrens syndrome. All agreed we need to
keep samples in the long term.

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Biomarkers are already being used in subpopulations. Ros Vallings said we must have
diagnostic guidelines for primary care doctors who do not have access to expensive testing.
The researchers felt people should meet the Fukuda and Canadian Clinical Criteria.
Dan Peterson said the VO2 max could be a cheap easy screening test- if it is normal, there is
no CFS. Kenny de Meirleir spoke about the days doctors saw “fever of unknown origin.” This
is now gone. We now have “fatigue of unknown origin”, but believes all cases have a
Don Lewis felt the Canadian criteria were very useful for the doctors as they could “tick the
boxes” and that it was important to find out the predisposing, perpetuating and
complicating factors.
Dr Klimas talked about the problem with the name- a name change committee met weekly
for 18 months, but public health would not accept their recommendations. She said
“fatigue” should go and stated there are not many more researchers in the field now than
when she started. K de Meirleir calls CFS “Gut- immune-neurotoxic disorder”.
R. Vallings uses letters to patients’ doctors to educate them. All agreed public perception of
the disease remained a huge problem. Dr Tate asked how the 17 million CFS patients
worldwide would feel about a name change. Someone suggested we employ a public
relations firm!

                            Day 2: Clinical Discussion
Dr. Klimas restated that there are no clearly established guidelines that are evidenced-based
for treatment. It is shocking that CBI and GET are the only approved treatments in many
She failed to get the CDC to establish an international group to develop guidelines so was
involved in convening the international group in Canada. She wants to develop something
workable for emergency departments.
Dr Peterson stated there is no licensed drug in the US for CFS – all are used “off label” which
is not evidence-based. He commented that Ampligen has been stuck at the FDA for 22 years
saying you can’t improve a drug for a disease that “doesn’t exist”.
It was noted that you can’t generalise a treatment from one population to the next eg
fluidrocortisone gold standard dose does not work in CFS.
Dr Klimas stated there are standardised testing instruments on the IACFS webpage which
can be used clinically and for research.
It was concluded to endorse the Canadian Criteria which should be called “international”,
that the CDS’s “empirical” criteria should not be used, off-label medications are necessary
and should be used.
The question was asked “why haven’t we done proper RCTs on treatments?” Dr. Don Lewis
said we must do things in a certain order, firstly deal with food intolerances (of his group of
patients 62 % had fructose and 40% had lactose intolerances). There was also a lot of egg
and casein intolerances. This leads to a sustained immunological challenge. Then, deal with
dysbiosis, with CFS patients having decreased gram-negative and increased gram-positive

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gut bacteria. Then deal with neurotoxic activity- he has found 85 % positive for hydrogen
sulphide which implies gut dysbiosis. He stated that food intolerance is the roots of the tree,
dysbiosis the trunk and branches the rest.
Several general practitioners discussed the cyclical worsening of CFS in some women.
It was suggested to develop national registries (there is one in the U.K.) which would
combine to form an international registry.
Dr Phillips suggested funding a review of all the current worldwide literature to get the
current state of play summarised and provide a direction for future research.
Dr Peterson noted in 10 and 20 year follow-ups, there was a “striking increase in lymphomas
(especially rare mantle-cell lymphomas) and brain tumours.” Dr de Meirleir has found an
increase in breast cancer under 30 years compared to non-CFS in Belgium, and an increase in
B cell lymphomas, however, a decrease in coronary artery disease as nitric oxide is
Dr Kwiatek believes at illness onset, there is an insult to the mid brain which regulates many
systems eg autonomic, so that the ANS is reset at illness onset.
Dr de Meirler’s population of the very ill shows all biomarkers worse eg higher in H2S which
correlates with light and noise sensitivity.
Dr Klimas said we should not generalise from the very ill- there are subgroups. Because the
disease is defined only after 6 months, it is hard to do the work to see how it evolved.
Perhaps it is an impossible task to find a “global biomarker.”

The meeting concluded after the group worked together to draft a press statement on the
                current status of ME/CFS and a list of future directions.

         Thanks to the chairs of the meeting, Prof Ken Donald and Prof Mel Miller.

     Thanks also to ME/CFS Victoria (Australia) and Susie Brookes and the fundraising
                         committee for enabling me to attend.

And, just to conclude this edition of Emerge, another article showing evidence of the huge
importance of abnormal gut bacteria and disturbed intestinal permeability, in conditions
closely related to ME/CFS/fibromyalgia and complex regional pain syndromes.

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 Goebl A, Buhner S, Schedal R, Lochs H, Sprotte G. Pain Management Centre, University
Hospital Wuerzburg, Department Gastroenterology, Hepatology and Endocrinology, Charle
                              Univeriltasmedizinc, Berlin.
                             Rheumatology 2008;47:1223-1227
Objectives: The pain intensity of patients with FM has recently been correlated with the
degree of small intestinal bacterial overgrowth (SIBO). SIBO is often associated with
increased intestinal permeability (IP). Increased IP may lead to the exposure of immune cells
to luminal antigens and consequent immune modulation.
It is currently unknown if IP is altered by FM. We therefore examined the IP in a group of
patients with primary FM and in 2 control groups, healthy volunteers and patients with an
unrelated chronic pain syndrome, complex regional pain syndrome (CRPS). We hypothesised
that patients with FM, but not healthy volunteers or CRPS would have altered IP.
Methods: IP was assessed using an established 3 sugar test.
Results: 40 patients with primary FM, 57 age and sex matched volunteers and 17 patients
with CRPS were seen. FM group-13 had increased gastroduodenal permeability and 15 had
increased small intestinal permeability: Volunteers – only 1 had increased IP. The IP values
were also unexpectedly increased in the CRPS group.

  Medical Pages compiled by Dr Nicole Phillips, Medical Editor, Emerge, quarterly
                    journal of ME/CFS Australia (Victoria).

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