Facts from Florida
Margaret Williams 16th
The 8th International
Association of Chronic Fatigue Syndrome (IACFS) Conference was held at Fort
Lauderdale, Florida, from 10th-14th January 2007. This
synopsis is not intended to be a detailed report of the Conference; it simply
lists some key points that people may wish to use in their dealings with
uninformed healthcare professionals. It is taken from the published reports of
conference attendees (including Dr Charles Lapp, Dr David Bell, Dr Rosamund Vallings,
Dr Lesley Ann Fein, Virginia Teague, Pat Fero, Cort Johnson, John Herd and
Pamela Young, whose various reports are on the internet (mostly on Co-Cure), to
whom grateful acknowledgment is made.
- The conference was attended by
over 250 clinicians and researchers from 28 different countries and there
was a strong sense that they were all co-operating to build on the science.
It is the science that has freed the world from any doubt that ME/CFS is a
legitimate disease with an aetiology that is not rooted in the psyche --
Japanese and Swedish research teams collaborated in a comprehensive study
of a neuro-molecular mechanism and concluded that ME/CFS is an organic
disorder. It was described as “this miserable illness”.
- The latest figures (January
2007) on the economic impact of ME/CFS in the US are between $22 billion
and $28.6 billion annually; in Japan, the figure is over $10 billion
annually. The Japanese Government recognises ME/CFS as a real threat not
only medically but also economically and has initiated a large research
programme into causation and treatment.
- One of the most striking
elements was the convergence of research findings: the three areas that
came up again and again were inflammation, mitochondrial abnormalities,
and vascular problems.
- Three separate research teams
found evidence of microvascular problems in ME/CFS.
- The significant confluence of
findings on elastase (a protease enzyme, i.e. it digests and degrades a
number of proteins, including elastin, a substance that supports the
structural framework of the lungs and other organs); vascular problems;
apoptosis (programmed cell death); free radical production (highly
damaging to DNA, to cell membranes and to proteins); and inflammation was
- Research findings addressed
many areas and provided yet more evidence that cognitive processing
differs in ME/CFS compared with controls; there is evidence of distinctive
chemical and molecular differences in ME/CFS patients; there is evidence
of the role of specific viral agents, and there is confirmation that
differences in gene expression exist between ME/CFS patients and healthy
controls, as well as between subgroups of “CFS”.
- The importance of sub-typing
was recognised and emphasised.
- Dr Ellie Stein from Alberta, Canada,
pointed out that suicide is the third leading cause of death in ME/CFS
(the others being cancer and heart disease).
- In ME/CFS, testing for elastase,
RNase-L, C-reactive protein, selected cytokines and NK cell activity are
recommended because they are objective markers of pathophysiology and
severity. In addition, an exercise test/re-test of cardiopulmonary
function is necessary because it is 100% objective and confirms reduced
functional capacity as well as post-exertional malaise for disability
purposes. Further, lipid abnormalities and evidence of metabolic syndrome
should be looked for.
- Researchers are developing
methods to measure cardiovascular and cardiopulmonary health in ME/CFS
patients, which relates to oxygen consumption.
- ME/CFS patients’ ability to
work is impaired, as shown by an abnormal exercise stress test. Margaret Ciccolella
and Christopher Snell et al from Stockton, CA, demonstrated that patients
show extreme abnormalities in a next-day/second session of exercise. They
do not recover in 24 hours. In one study, only one patient had recovered
to baseline within 48 hours. These changes in serial testing point to a
significant and confirmable physical abnormality, verifying the cardinal
symptom of post-exertional malaise. This test/retest exercise test is 100%
objective and can prove to the disability companies that ME/CFS is neither
malingering nor faking. In ME/CFS patients, the measurements declined by
about 25%, far more than in other significant diseases such as COPD and
even heart failure.
- Post-exertional malaise
following exercise challenge results in fatigue, light-headedness,
vertigo, joint pain, muscle pain, cognitive dysfunction, headache, nausea,
trembling, instability, and sore glands.
- In ME/CFS patients, there is
cellular hypoxia — oxygen is delivered to the cells of the heart, brain,
skeletal muscle and other organs, but the process of turning oxygen into
energy is derailed.
- Graded exercise therapy is
ill-advised — if a patient has abnormal oxygen consumption, muscles will
not have enough oxygen and exercise will result in relapse.
- A US NIH-funded trial by Barry
Hurwitz, a colleague of Professor Nancy Klimas at the University of Miami,
found that 70% of ME/CFS patients have a low red blood cell volume.
Treatment to increase blood volume was ineffective in respect of exercise
tolerance and fatigue.
- One of the highlights of the
conference was the presentation of Dr Vance Spence’s work (University of Dundee)
on inflammation and arterial stiffness in patients with ME/CFS – arterial
stiffness is rarely found in adolescents, but in ME/CFS these young
patients had higher levels of arterial stiffness than diabetic patients.
This work looked at inflammatory factors (free radical by-products and
C-reactive protein, an inflammatory marker) and found abnormally high
levels of free radical by-products and C-reactive protein in patients but
not in controls. C-reactive protein levels were significantly correlated
with increased arterial stiffness. A likely cause is elastase. Elastase is
a central factor in Professor Kenny de Meirleir’s RNase-L paradigm (see
below), and Dr Baraniuk’s cerebrospinal fluid proteome study suggests elastase
is implicated in blood vessel problems in the brain of ME/CFS patients.
The logical consequences of increased arterial stiffness are exercise
intolerance and diastolic (cardiac) dysfunction. The circulatory problems
seen in ME/CFS may originate in endothelial cells lining all blood
vessels. These cells are involved not only in opening and closing blood
vessels but in the immune response as well, and they are often attacked by
- Dr Paul Cheney (Mayo Clinic)
found evidence of diastolic (cardiac) dysfunction in ME/CFS, with evidence
of another cardiac abnormality (patent foramen ovale, or PFO). This
results in hypoxia (low oxygen levels relative to metabolic needs).
- Cheney stated that the cardiac
index of ME/CFS patients is so severe that it falls between the value of
patients with myocardial infarction (heart attack) and those in shock.
- Mark van Ness from the
University of the Pacific found that maximum aerobic capacity (VO2
peak) is reduced in ME/CFS compared with sedentary controls.
- Van Ness found that oxygen
capacity at the anaerobic threshold is reduced in ME/CFS.
- Van Ness also found that serum
lactate is elevated, suggesting an abnormally early shift to anaerobic
- In a subset of patients, Martin
Lerner (Wayne State University, Detroit) described persistent EBV and/or
CMV in ME/CFS patients: in addition to having high titres, all 37 patients
studied had an elevated heart rate at rest, recurrent T-wave inversion on Holter
monitoring, cardiac abnormalities and/or biopsy-proven cardiomyopathy.
Symptoms included not only tachycardia but chest pain and syncope.
- According to Lerner, all ME/CFS
patients have abnormal T waves; inversion is seen in 96%; there is resting
tachycardia. Cardiac biopsies show fibrosis, myofibre disarray and fatty
- New methods in viral studies
using refined technology show further abnormalities in subsets of ME/CFS
patients. Increased use of instruments like MRI, SPECT/SPET, PET and fMRI
show some of the abnormalities in functioning that patients with ME/CFS
experience on a daily basis but these may not have practical application
if a patient cannot have this testing done. A number of abnormalities with
reduced responsiveness on fMRI is an essential feature of ME/CFS.
- Brain imaging shows that,
amongst other abnormalities, ME/CFS patients have reduced blood flow to
the brain (especially to areas that are involved in autonomic nervous
system functioning and in sleep, concentration and pain, including the
pre-frontal cortices, the anterior cingulate and the cerebellum); altered
patterns of brain activation; reduced grey matter volume; altered serontonergic
neurotransmission and reduced acetyl-carnitine uptake.
- A collaboration of researchers
from Spain, Belgium and Australia used SPET scanning to observe patterns
of brain activity; they found that the brain abnormalities correlated with
abnormal immune results.
- Patients with ME/CFS require
more brain regions to perform tasks, ie. they have to work harder to
achieve the same results as healthy controls.
- One particular area of the
brain – the Wernicke area, essential for understanding and formulating
coherent speech—showed evidence of reduced activity after exercise.
- Proton resonance spectroscopy
showed greatly increased levels of brain metabolites (lactate levels were
300% higher than in controls).
- According to Dr Tae Park from South
Korea, the unexplained bright spots on MRI scans of some ME/CFS patients
are evidence of an “arteriolar vasculopathy” or a blood vessel disease. He
believes ME/CFS is a “systemic micro-vascular inflammatory process” – a
process that would affect not only the brain or the heart or the muscles,
but potentially every organ system in the body. Dr Park found not only
capillary inflammation and perivascular cuffing (the accumulation of
immune cells that surround injured blood vessels), but that all the ME/CFS
patients in his study demonstrated remarkably reduced renal blood flow. Dr
Park noted that diabetics with renal vascular disease also complain of
- Dr Hiro Kuratsune from Japan
gave a summary of what is known about brain function in ME/CFS. It has
been known for over a decade that frontal and temporal lobe blood flow is
reduced in ME/CFS, and that exercise exacerbates this reduced blood flow
for up to 72 hours. The new evidence is that elevated elastase and RNase-L
levels correlate with reduced blood flow. It is known that the MRI is
abnormal in the majority of people with ME/CFS due to numerous T2 weighted
hypertintense foci, with evidence of demyelination.
- Patients with more brain
abnormalities tend to be more physically impaired.
- The remarkable similarity in
the brain images of patients with ME/CFS and multiple sclerosis was noted.
- Dr Gudrun Lange from New Jersey,
USA, stated what can be said with certainty about the central nervous
system findings in ME/CFS:
- the major cognitive problem
seen is in information processing
- studies showing reduced
cerebral blood flow are starting to show consistency
- there is a problem with serotonergic
neurotransmission in the hippocampus and anterior cingulate regions
- there are spinal fluid
- fMRI studies are showing
altered patterns of brain activation.
- Proteomics is the study of
proteins made in the cell, particularly their structure and function.
Investigations into proteomics in ME/CFS are surging forward in many
- Proteins predictive of ME/CFS
were found in patients that were absent in healthy controls.
- Dr James Baraniuk from Georgetown
University, Washington DC described the (quote) “unbelievable” finding of
unique markers in the cerebrospinal fluid of ME/CFS patients that are
completely absent from the control group.
- The proteomic biosignature of
ME/CFS in the cerebrospinal fluid shows:
- a protease/antiprotease
imbalance is present: alpha 2 macroglobulin (anti-protease) and orosomucoid
2 (anti-protease); this implicates increased elastase production
- several proteins suggest that amyloid
deposition in the blood vessels of the brain is causing
micro-haemorrhaging (amyloidosis is the deposition in the tissues of a
starchy, waxy protein substance; the organs most affected are the liver,
kidneys, spleen and heart; it occurs in conditions of chronic
- one protein present suggests
altered (increased) rates of apoptosis (ie. programmed cell death, a
well-documented finding in ME/CFS)
- another protein present
suggests free radical production is occurring
- another protein suggests
problems with vasoconstriction and endothelial damage (pigment epithelial
derived factor and endothelial proliferation associated with vascular dysregulation)
- another protein is associated
- One protein that was found –
keratin – is of particular interest: it is associated with inflammation of
the leptomeningeal cells in the membranes covering the brain and spinal
- This proteome is not found in
- Of special interest was the
study from Stanford University School of Medicine by Dr Jose Montoya: this
was a groundbreaking study on anti-viral therapy for patients with
elevated antibodies to HHV-6 and EBV; with a $1.3 million grant, this
study will shortly be repeated among a subset of patients who have
viral-induced dysfunction of the central nervous system.
- Japanese researchers looked at
the reactivation of HHV-6 and HHV-7 in ME/CFS. These viruses have
life-long latency. It is vital to distinguish between chronic, active and
- Dr Dharam Ablashi from Santa
Barbara, USA, showed that RNase-L was found to correlate with HHV-6
infection in ME/CFS and that RNase-L protein is a marker for active
- Some patients clearly have a
persistence of virus in their brain.
- Enterovirus infections have
previously been reported in UK studies but have not been much explored by
US researchers. Enteroviruses are a genus of RNA viruses that includes
echovirus, coxsackie virus and poliovirus. In a recent US study by John Chia
from California of 108 patients with ME/CFS who underwent gastric
biopsies, 100 revealed chronic inflammation and 80% were positive for VP1
(enteroviral capsid protein – first used by Professor James Mowbray et al
in the UK in 1988). Enteroviral RNA was detected in 33% of patients.
- Symptoms observed in ME/CFS are
compatible with a viral aetiology.
- Many infectious agents have
been cited as implicated in ME/CFS including EBV, Lyme, parvovirus, enteroviruses,
Q fever, RRV, mycoplasma and HHV-6.
- Over the last ten years there
has been increasing evidence that infection is most likely to be a prime
cause of ME/CFS.
- As noted in the Virology
section (above), many ME/CFS patients have persistent or intermittent
gastrointestinal symptoms: VP-1 was positive in 80% of patients and enteroviral
RNA was detected in a number of stomach biopsies, compared to none in
- Professor Kenny De Meirleir
from Brussels (but now in the USA) found that 80% of ME/CFS patients
exhibit problems with digestion: regular findings of antibodies (IgA, IgM)
to intestinal bacteria in the blood of patients indicate disturbance of
the gut permeability barrier; this dysfunction results in intestinal
bacteria entering the blood stream.
- Professor Kenny De Meirleir
also showed that fructose malabsortion is very common in ME/CFS patients
and can lead to intestinal dysbiosis; careful diet is therefore required.
- Nine clinical sleep
abnormalities exist in ME/CFS. Actigraphy studies show four main types: hypersomnia;
severe insomnia; “tired but wired” (hyposomnia) and delayed sleep.
- Studies by Sieki Tajima from Osaka,
Japan, revealed by autonomic analysis in ME/CFS patients that poor sleep
may be due to a lack of parasympathetic activity during attempted sleep
- Dr Joan Shaver from the University
of Illinois, Chicago, found that there is decreased growth hormone
production during sleep.
- Various methods to study
fatigue were described by Professor Y Watanabe from Osaka, Japan, such as
cortical function, autonomic nerve function, biochemical markers in plasma
and saliva, and scans of brain function.
- Researchers at De Paul
University, USA, have shown there are five types of fatigue associated
- Dr Garth Nicolson from the
Institute for Molecular Medicine, CA, showed that fatigue is caused by
damage to the mitochondria, thus impairing the patient’s ability to make
ATP and NADH, and Dr Jacob Teitlebaum from Annapolis, Maryland, showed
that patients have decreased ATP.
- Pain was described as a major
feature in many aspects of ME/CFS. There is a pain matrix in the brain and
the experience of pain occurs as a result of central processing via a CNS
network. Multi responses may occur in different organs.
- J.Alegre-Martin from Barcelona,
Spain, studied neurocognitive impairment in ME/CFS and found considerable
cognitive deterioration, with a difference in processing between right and
left brain hemispheres.
- A study by R Shoemaker
(Pocomoke, USA) looked at the systemic inflammation in ME/CFS caused by
C4a and suggested that the central nervous system correlates of cognitive
dysfunction have an inflammatory basis.
- There are elevated
pro-inflammatory cytokines in patients with ME/CFS. (Cytokines are immunologically-based
chemicals that can cause viral symptoms such as sore throat, swollen
glands and flu-like symptoms often seen in ME/CFS).
- Brian Gurbaxani and Suzanne
Vernon et al (CDC, Atlanta) demonstrated that increased levels of IL-6
correlate well with C-reactive protein (CRP) and are proportionate to
symptom severity in ME/CFS.
- Barry Hurwitz from the University
of Miami showed that pro-inflammatory cytokines have a secondary effect
in reducing red blood cell (RBC) volume, due to probable suppression of
RBC production in the bone marrow.
- Studies by Professor Kenny De Meirleir
et al (Belgium) found that the majority of ME/CFS patients had increased
rates of RNase-L activity (83%), RNase-L fragmentation (88%) and a massive
95% had increased elastase levels. These abnormalities could contribute to
the muscle symptoms seen in ME/CFS.
- Mary-Ann Fletcher, a colleague
of Nancy Klimas from the University of Miami, found that perforin (a
molecule in cytotoxic lymphocytes) is low in ME/CFS, as are NK cells.
- There is increased incidence of
thyroid malignancy associated with ME/CFS. Dr Byron Hyde from Canada
stressed the importance of evaluating this by thyroid ultrasound and
needle biopsy, despite euthyroid serum results.
- Brigitte Evangard from Stockholm,
Sweden, found increased levels of Candida albicans in ME/CFS patients (a
sign of a disrupted immune system).
- Anthony Komaroff (Professor of
Medicine, Harvard) summarised the immune abnormalities that have been
demonstrated in ME/CFS. These include activated CD8 (T cells); poorly
functioning NK cells; novel findings –seen only in ME/CFS -- of
abnormalities of the 2-5A pathway (RNase-L ratio); cytokine abnormalities
(pro-inflammatory dysregulation); increased TGF, and 27 times more
circulating immune complexes than in controls.
- Paul Nestadt from Mt Sinai
School of Medicine, NYC, used Magnetic Resonance Spectroscopy to
demonstrate that lactate is increased and N-acetyl-aspartate (NAA) is
reduced in the brain of people with ME/CFS. High lactate levels
corresponded with the level of fatigue and were not abnormal in persons
with depression or anxiety. These findings are further evidence that
ME/CFS is not psychiatric in origin.
- A significant proportion of
patients had elevated brain ventricular lactate. Marked differences in hippocampal
glutamate helped differentiate between patients with ME/CFS with and
without depression. These differences support neurobiological distinctions
between “pure” ME/CFS and CFS with psychiatric co-morbidity.
- The high lactate levels appear
to reflect the existence of exhausted cells in the brain.
- The neuro-endo-immune
dysfunction in ME/CFS appears to be related mostly to the abnormal
activity of glutamate and serotonin, acetlycarnitine, transforming growth
factor-B and interferon.
- Genomics is defined as the study
of the function and interactions of genetic material in the genome,
including interactions with environmental factors. Genetics is the study
of a single gene.
- Both play a significant role in
ME/CFS. Some people have a genetic predisposition: statistical analyses on
over 600 people with ME/CFS found that their closest relatives had higher
rates of migraine, irritable bowel syndrome, Raynaud’s disease, TMJ
disorder, osteoarthritis and myalgia.
- A study by Rosemary Underhill
from New Jersey looked at the prevalence of ME/CFS in the offspring of
mothers with the disease and found that 24% of affected mothers had
offspring with documented ME/CFS.
- A Japanese study looking to
identify unique gene expression profiles found that being physically
exhausted is not an extension of being tired – it elicits a unique
response from the body. These researchers found nine genes with altered
activity levels in ME/CFS patients, none of which were found in healthy
controls 24 hours after exercise. These genes are involved in mitochondrial
functioning; neurotransmission; the immune system; metabolism and the
endocrine system – a very common cast of characters in gene expression
studies in ME/CFS patients.
- Dr Jonathan Kerr from London
stated that his gene expression studies are finding three main
abnormalities in ME/CFS patients: these involve the immune system,
mitochondrial function and G-protein signalling. There are seven genes upregulated
in ME/CFS – those associated with apoptosis, pesticides, mitochdonrial
function, demyelination and viral binding sites. Kerr mentioned three
genes in particular: gelsolin, which is involved in apoptosis and amyloidosis;
one that is upregulated by organophosphates, and a mitochondrial gene
involved in the demyelination of nerves.
- The new paediatric diagnostic
criteria from Professor Jason et al (De Paul University) means there is
now a science-based instrument that will be able to correctly diagnose
children and adolescents with ME/CFS.
- In contrast to the US and
countries such as Australia, South Korea, Japan, Sweden, Belgium, Chile,
Latvia and Spain (to name just some), the UK Government is resistant to
funding any biomedical research into ME/CFS and financially favours
studies into behavioural modification regimes for such patients.
- Dr Ellie Stein, a psychiatrist
from Canada, was specific about such behavioural modification programmes.
Neither ME/CFS nor fibromyalgia is considered a psychiatric disorder. She
stated that unfortunately, many medical practitioners conclude erroneously
that psychiatric care and vigorous exercise are “the cure” for ME/CFS.
Previous CBT/GET programmes were based on the false assumption that
avoidance of activity, illness severity and increased attention to
symptoms were causing or perpetuating symptoms, when in reality they were
the result of the illness. Of seven controlled studies using CBT, only
four were positive and most were inconclusive or poorly done. Five studies
of graded exercise in ME/CFS patients showed no improvement in pain,
sleep, autonomic function, immune system function or cognitive symptoms.
Stein emphasised that neither CBT nor GET works well because many ME/CFS
patients do not have dysfunctional beliefs, many are already functioning
at maximum activity levels, and exercise makes some patients worse. Whilst
CBT and GET are the most studied behavioural interventions, results are
Despite the significant
biomedical abnormalities found in ME/CFS that have been published over the last
two decades and despite the vast amount of research evidence presented at so
many international conferences over so many years and despite the $4.5 million
public awareness campaign bankrolled by the US Centres for Disease Control,
some clinicians – in this case Peter Manu, Associate Professor of Medicine and
Psychiatry at Yeshiva University’s Albert Einstein College of Medicine and
Director of Medical Services, Hillside Hospital, Long Island Jewish Medical
Centre, New York – still refuse to accept the scientific evidence. On 14th February 2007, Manu went on record as affirming: “I personally believe the
CDC’s emphasis on (ME/CFS) has been wrong from day one. I don’t think there is
much to it” (The Times, Frankfort, Indiana, 14th February 2007).
There speaks the difference
between psychiatry and science.
Corrections and Clarifications
Margaret Williams thanks those who have queried her reference in her article "Facts from Florida" to Dr P Chaney being at he Mayo Clinic.
She wondered about this herself but accepted in good faith the notes of Dr
Lesley Ann Fein which clearly stated that Dr Cheney was at the Mayo Clinic.
Margaret also apologises for the numerous typing errors including "peforin"
which should of course be perforin and "disarry" which should of course be