• A review of the clinical aspects of ME/CFS
• Intracellular immune dysfunction in ME/CFS
• The development of clinical services for those with
  ME/CFS
• Patient centered research and clinical aspects
• Treatments targeting the methylation cycle
• The care pathways adopted in clinical practice
• Clinical studies focussing on autonomic issues
• A centre of excellence
• Current research taking place in Nevada
• Vascular and inflammatory aspects of ME/CFS
• A review of molecular studies in ME/CFS
• The Swedish Twin registry--looking for a biomarker
• Q fever, Rickettsia and CFS

          ```````````````

Introduction

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.


A review of the clinical aspects of ME/CFS

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 – 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 ERß) receptors
are implicated in several diseases. There was
reduced expression of ERß 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.





As always when a conference ends, there is a sense
of sadness saying goodbye to old friends again, but
inevitably 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


6 May 2008