Introduction
Part 1 of these extracts from the
grey literature on ME/CFS from 1956 – 1990 can be seen here -
click here
Part 2 of these extracts from
1991 – 1993 can be seen here -
click here
1994:
In its issue of Winter 1994 (ie.
early 1994), the CFIDS Chronicle reported on meetings in
September 1993 at the CDC and on a two-day workshop held in
November 1993 at the NIH on the clinical management of ME/CFS.
Dr Dedra Buchwald listed commonly reported symptoms not
included in the case definition, notably shortness of breath,
unsteadiness, morning stiffness, blurred vision and dizziness,
and she noted the presence of multiple chemical sensitivity.
She stated that “improvement may represent an accommodation
of limitations rather than a disappearance of symptoms”.
Dr Anthony Komaroff provided a review of the respiratory,
neurological, rheumatic and gastro-intestinal symptoms of
ME/CFS, and emphasised that he did not find that ME/CFS
patients over-report symptoms that are not common to the illness.
Dr Jonathan Rest reminded clinicians that patients are
usually more sick than they appear. Dr Paul Goodnick
noted that CFS patients go to great lengths to help themselves,
unlike patients with classic depression, and made an appeal to
change the name of the disease, stating that this single act
would greatly enhance physicians’ understanding of the
seriousness of the illness. Seemingly dismissive of the
biomedical evidence of expert clinicians, psychiatrist Dr
Michael Sharpe contended (i) that he could potentially cure CFS
with CBT; (ii) that factors correlating with worsening of the
illness include a belief that it is caused by a viral infection
and by belonging to a self-help group, and (iii) that those who
do not improve with CBT may have a personality disorder. Dr
Phillip Peterson questioned the merit of trying to change
patients’ beliefs about the disease when the mechanisms of it
were not yet known, saying he had found no other disease with
such global immune disturbance.
1994:
On 14th May
1994 The New Scientist published an article by Renee
Twombly (The trouble with ME: New Scientist, Volume 142, No:
1925) drawing attention to a forthcoming conference on ME/CFS to
be held in Dublin that month and noting that it was one of the
few conferences on ME/CFS to be held outside the US. Twombly
quoted Peter Behan, Professor of Clinical Neurology at the
University of Glasgow: “Behan says that several papers to be
presented at the conference offer new evidence that the illness
is due to factors that upset a cell’s production of energy….
‘All this evidence tells us that the mitochondria are sick in
the CFS patients we studied’, Behan explains….Behan believes
that more support for his theory is provided by work at the
University of Leeds, which suggests that muscle cells in
patients with CFS contain inadequate supplies of the ions they
need for the production of ATP. They also found low levels of
phosphate, which is involved in the production of ATP”. Twombly
mentioned the views of Dr Keiji Fukuda of the CDC (whose case
definition was published that year in the Annals of Internal
Medicine) and Dr Peter Manu (Director of Medical Services at
Hillside Hospital, New York), noting that Fukuda “is not
ready to accept Behan’s theories (and) his unwillingness to
exclude psychological factors mirrors the primary position of
the National Institutes of Allergy and Infectious Diseases”
and that Manu “doesn’t need any convincing that CFS has a
psychological component….Behan, however, dismisses any idea that
CFS is controlled by the mind (and) sees dangers in following
the psychological approach: ‘It’s absolutely retrogressive to
suggest that CFS is in the heads of patients’, says Behan. ‘I
have seen patients commit suicide, or have been otherwise
destroyed, because some professor has diagnosed them as having a
psychiatric illness’ ”.
1994:
The International
Meeting on Chronic Fatigue Syndrome was held in Dublin on 18th-20th
May 1994 under the auspices of the World Federation of
Neurology. It was reported by the ME/CFS charities: in its
newsletter InterAction No: 16, the charity Action for ME (AfME)
published a report on the conference by Dr Anne Macintyre and
Doris Jones (who noted that the meeting was attended by about
170 delegates from Europe, North America, South Africa and
Australia), and Stephanie Woodcock of the ME Association
reported on it in two issues of its magazine “Perspectives” (in
June and December 1994).
There were 24 poster
presentations and 46 verbal presentations, including those by Dr
Anthony Komaroff from Harvard Medical School, Boston, (who spoke
on case definitions); Dr Paul Levine from the National Cancer
Institute, Maryland (the history and epidemiology); Dr Irving
Salit from the University of Toronto (precipitating events);
Professor Ted Dinan from London (the neuroendocrinology of the
disease); Dr Charles Poser from Harvard (the differential
diagnosis between ME/CFS and MS); Dr Frances Aitchison from
Glasgow (brain scans on ME/CFS patients); Dr Jay Goldstein from
California (cerebral blood flow [CBF] by SPECT scans); Dr
Russell Lane from Charing Cross Hospital Medical School, London
(defective muscle metabolism and the presence of enterovirus RNA
in the muscle); Dr Wilhelmina Behan from Glasgow (mitochondrial
changes); Dr Hirohiko Kuratsune from Osaka University, Japan (acylcarnitine
deficiency); Dr T Majeed from the Department of Neurology,
University of Glasgow (who also spoke on abnormal intracellular
acylcarnitine); Dr Layinka Swinburn from the Department of
Chemical Pathology and Immunology, St James University Hospital,
Leeds (insufficient ATP and the consequences); Professor Andrew
Smith from the University of Bristol (abnormalities in objective
measures of cognitive impairment), and Professor Dr Rainer Ihle
from Dusseldorf (immunological changes, hormonal disturbance and
increased levels of toxins, and on myocardial SPECT scans). Drs
Fukuda and Peter White also gave presentations, Dr White’s talk
referring only to patients who were fatigued after proven
glandular fever.
Notable points made in 1994 which
17 years later have still not entered mainstream medicine (due
largely to the influence of the Wessely School) include the
following:
Dr Anthony Komaroff
said that symptoms which are not currently part of the case
definition such as anorexia, nausea, alcohol intolerance and
parasthesaias may be added to a revised case definition.
Dr Paul Levine from
Maryland warned that “CFS is not one disease, and your
diagnosis may depend on who you see and where – a neurologist’s
or psychiatrist’s group of patients are not going to have the
same sort of CFS as those of a rheumatologist”. He said
that ME/CFS is “an unusual and inappropriate immune response”.
Dr Jay Goldstein
from Los Angeles had done hundreds of brain scans on ME/CFS
patients and reported that SPECT scans show obvious
abnormalities. He said that the overall patterns of rCBF
(regional cerebral blood flow) were distinctly different in
depression compared with CFS, and that patients with (ME)CFS
who have co-morbid fibromyalgia have more severe hypoperfusion
than patients with (ME)CFS alone. He said it is possible to
differentiate (ME)CFS from depression by looking at the
hypoperfusion pattern (in 2011 in the UK, scans to aid
diagnosis of ME/CFS are still proscribed by the NICE Clinical
Guideline 53, again due to the influence of the Wessely School
who insist that ME/CFS [or “CFIDS”, or “CFS/ME” or “CFS”] is a
behavioural disorder).
Dr Frances Aitchison,
a radiologist from Scotland, said that she had performed both
MRI and SPECT scans on ME/CFS patients and that the
abnormalities related to areas of hypoperfusion (ie. low
oxygenation levels); the areas are principally in the temporal
lobes, occipital lobe and the left frontal lobe and these
abnormalities are statistically significant.
Dr Russell Lane,
a neurologist from London, reported on exercise studies done by
his group and said that 32% of (ME)CFS patients tested had
abnormal SATET responses (sub-anaerobic threshold exercise
testing) suggesting defective muscle metabolism and 21% were
positive for enterovirus in muscle; there was a significant
association between abnormal SATET and enterovirus (being
greatest in patients with a greater lactic acid response to
exercise). Heart rate response to exercise, as well as muscle
fibre morphometry, showed these abnormal lactate responses could
not be due to deconditioning: he stressed that morphologically,
most of the (ME)CFS patients had muscle hypertrophy, whereas
unused or deconditioned muscles would be expected to show
atrophy. He concluded that a significant proportion of ME/CFS
patients have evidence of impaired aerobic muscle function.
Dr John Gow
from Glasgow reported that evidence of enteroviral sequences can
be found in the muscles of up to 82% of (ME)CFS patients and
that the persistence of a virus may upset cell homeostasis.
Dr Wilhelmina Behan
from Glasgow said that electron microscopy has shown
abnormalities of mitochondria: enlargement, change of shape and
proliferation of cristae, giving an abnormal honeycomb
appearance, was found in up to 70% of muscle biopsies (the
abnormal mitochondria were about twice the size of normal). The
structure of mitochondria is very closely linked to energy
metabolism and Dr Behan concluded that the findings suggest an
interference with energy metabolism. Cell cultures were
established from 10 muscle biopsies and severe decrease in cell
respiration was found in two of the four samples tested. Serum
acylcarnitine is deficient in CFS patients. A mtDNA
deletion was found in four patients but in none of the
controls. These data on mitochondria suggest that CFS may be
precipitated by environmental factors in individuals who are
genetically predisposed.
Professor Dr Rainer Ihle
from Germany said that data on 375 CFS patients demonstrated
various immunological changes and autoantibodies (especially
antinuclear antibody and microsomal thyroid antibodies) in an
abnormally large proportion of CFS patients, suggesting impaired
immunity and facilitating transition to autoimmune disease
(“On the basis of these immunological serological and
organ-specific findings, which affirm previously published
results, it would appear that the organic nature of the
pathogenesis of CFS has now been demonstrated”). He
also found vitamin and mineral deficiencies, hormonal
disturbances, and increased levels of toxins such as wood
preservatives and pentachlorophenol. SPECT scans showed
reduced rCBF in 83%, and MRI scans showed focal changes in 30%.
SPECT scans of the myocardium showed conspicuous changes in 73%
during exercise. Professor Ihle reported that 75% of his cohort
experienced dizziness and 53% had hair loss. He said that
future studies should differentiate subgroups of CFS, which
would improve targeting of therapies (this should be
compared with the Wessely School’s insistence that there is no
need for subgrouping and their intention to classify all states
of medically unexplained “fatigue” as a somatoform disorder).
Dr Layinka Swinburne
from Leeds confirmed that the distinct symptom of ME is
fatigability of muscle after minimal exercise, with slow
recovery before muscle power is restored, and said that Dr
Melvin Ramsay called this phenomenon the ‘sheet anchor of
diagnosis’. She presented evidence that the basis of the
fatiguability is a defect in the regeneration of high energy
phosphates, especially ATP, and that such an impairment would
generate changes in membrane bound transport and ion movement,
leading to chronic intracellular ion depletion (phosphate,
potassium and magnesium), with further impairment of
mitochondrial function; physical activity would produce
greater depletion, leading to interference with many other
functions such as immune reactions, hepatic detoxification, gut
motility, neurotransmitter function, maintenance of red cell
shape and tissue respiration.
Dr Sean Coyle,
an associate of Dr Swinburne, noted that serum potassium and
phosphate levels have been shown to be decreased in ME and that
renal tubular handling of phosphate was low, suggesting an
inappropriate loss of phosphate in patients with ME. He noted
that low phosphate levels could affect every cell in the body
and may cause bone factures, weakness, fatigue, abnormal
pulmonary function, low blood pressure and depressed cardiac
stroke volume, as well as cognitive dysfunction.
Dr Jay Levy
from San Francisco presented serological and immunological data
from (ME)CFS patients, pointing out that, by lymphocyte
phenotype analysis, the T8 suppressor subset was decreased, a
notable and important finding, since others have found the
opposite (perhaps due to the heterogeneity of subjects). He also
found that activated T cells were increased, with the most
pronounced increases seen in the sickest patients, and that NK
cell activity and cytotoxic lymphocyte activity were both
depressed in (ME)CFS patients.
Dr Hirohiko Kuratsune
from Japan expanded on his 1992 presentation at the Albany, New
York; he found in a Japanese study that most (ME)CFS patients –
male and female -- had serum acylcarnitine (AC) deficiency, and
that the degree of AC deficiency related to the severity of
the symptoms; no AC deficiency was found in bed-rest patients
without (ME)CFS, implying that low AC in (ME)CFS is not due to
physical deconditioning. He pointed out that the sicker
patients have lower AC levels. There was no urinary increase in
AC, thus the deficiency could not be attributed to urinary
loss. Perhaps unfortunately, AC levels are not specific for
(ME)CFS as they also occur in infection, malabsorption, AIDS
and other immune dysfunction syndromes.
Dr Charles Poser
from the US, an internationally renowned neurologist
specialising in MS, found similar brain lesions in both
ME/CFS and MS patients, suggesting a chronic and recurring brain
disorder. In his view, the fatigue in both disorders is
indistinguishable. He reported authoritatively that atypical
reactions to many different medicines and drugs is virtually
pathognomonic of ME/CFS.
Professor Ted Dinan
from London reported on abnormal neuroendocrine findings and
said that the pattern of neuroendocrinological response
appears to be unique in ME/CFS patients, with an enhanced
prolactin (an important stress hormone) response when challenged
by the anti-anxiety drug buspirone, and a blunted response to
dexamethasone, with ME/CFS patients having lower baseline GH
(growth hormone) levels than either normal controls or depressed
patients.
Professor Andrew Smith
from Bristol said that over 5 or 6 years he had demonstrated
significant impairments of motor function and abnormalities on
objective measures of memory and attention, and that central
nervous system functioning is definitely abnormal in ME/CFS
patients.
Professor Mark Demitrack,
a US psychiatrist, reported that patients with major affective
disorders tend to have hypercortisolism, whereas patients with
(ME)CFS have adrenal insufficiency (ie. hypocortisolism), with a
30% drop in overall cortisol output. He concluded that “(ME)CFS
patients cannot be absorbed into any one pre-existing
psychiatric diagnostic category”.
The Dublin meeting was an
important international conference but apart from derisory
comments in the medical trade press, it received almost no
mention in the mainstream media or medical journals.
The medical trade press was
factually incorrect and scathing; “GP Medicine” carried an
article by Paul Haines with banner headlines proclaiming: “Research
fails to impress”, which went on to disparage the entire
conference: “In Dublin last month, when the city hosted the
first world conference on myalgic encephalomyelitis (this
was incorrect – the first World Symposium on ME was held four
years previously in April 1990 at the University of Cambridge),
one old woman claimed to know the condition’s origin…Her point
of view was only slightly less conventional than many of the
other theories that were expounded at the conference…The
American presence was enormous, reflecting the enthusiasm with
which that country has embraced the subject of ME. Three or
four delegates carried video cameras to record each other….Each
speaker presented his pet theory with some research data to back
it up. But once the talk was over….there seemed little lasting
interest….There were countless presentations about viral
triggers and neuro-endocrine activity”. Despite the
biomedical evidence that was presented, the article erroneously
asserted: “Disappointed doctors are none the wiser after ME
conference”.
In the “Medical Matters” section
of its magazine “Perspectives” (September 1994) the medical
advisor to the ME Association, Dr Charles Shepherd, wrote: “Sadly,
the conference failed to achieve very much publicity in the
medical press. Having personally contacted the editors of most
of the mainstream medical journals, it was very disappointing to
find little or no coverage being passed on to a wider medical
audience”. Commenting on an Editorial in GP, Dr Shepherd
said that it “appeared to be written by someone who has an
extremely biased view of the whole ME debate. Titled ‘Doctors
can be right too’, the editorial went on to describe, quite
inaccurately, a meeting attended by ‘hundreds of hangers-on’ and
papers being presented by ‘those who measured and pampered the
afflicted’ ”.
(Later that same year, on 20th
November the Sunday Telegraph reported on a conference attended
by 150 British psychiatrists held on the island of Jersey,
proclaiming: “ME is just a myth….A group of leading
psychiatrists has overwhelmingly concluded that ME is all in the
mind”).
1994:
The Spring 1994 issue
of the CFIDS Chronicle carried an article by Dr Paul Cheney of
Charlotte, North Carolina, on the likely pathophysiological
mechanisms underpinning ME/CFS, in which he drew attention to
key symptoms. These most commonly include…subnormal
temperature; myalgias (especially of axial skeletal muscles);
deep bone pain in the extremities; arthralgias; pressure
headaches; sleep disorders; enlarged and/or painful lymph nodes;
night sweats; new onset or worsening of allergies; dizziness or
balance problems; migrating sensory dysesthesias; sensitivities
to heat, cold, light, sound and chemicals; alcohol, food and
drug intolerance; visual disturbances; disabling cognitive
impairments; acneform, herpetiform and morbilliform skin
eruptions, and an assortment of breathing, cardiac,
gastro-intestinal and genitourinary symptoms.
Amongst the most common physical
findings (ie. signs detectable by a clinician) are
palpable, slightly enlarged discoid-shaped and tender posterior
and middle cervical lymph nodes, which are almost always
left-side predominant. This left-sided predominance and
lymphatic channel tenderness extending into the medial
supraclavicular area strongly suggests increased lymph
production – lymphatic fluid carries cytokines, and in an immune
activation state, lymphatic flow increases, causing fluid
retention and tissue oedema commonly seen in ME/CFS which would
produce lymphatic congestion
(over 90% of lymph flows back into the blood stream just below
the left collar-bone, so if there is increased flow, congestion
will occur within lymph node chains closest to that juncture,
hence left-sided dominance of lymph node tenderness in the
supraclavicular area).
Other common physical findings include a
higher than normal incidence of hyper-reflexia (80% of patients)
and abnormalities of vestibular function with an inability to
maintain the Romberg, tandem or augmented tandem stance
positions (which clinically support the evidence of central
nervous system injury observed on functional and structural
brain scans).
In an interview with Dr Cheney
published in the same issue, he said that ME/CFS patients
have limited anti-oxidant reserve, and this is why exercise
sends them into relapse.
The same issue carried an article by Dr
Nancy Klimas et al reporting on the association between HLA
(histocompatibility locus antigen) Class II antigens and
CFIDS/ME/CFS. Klimas noted that her group and others have
reported a strong association between immune dysfunction and a
serological viral reactivation pattern in these patients
similar to that observed in conditions such as chronic active
hepatitis and systemic lupus erythematosus in which a
definite association between a particular HLA-DR/DQ haplotype
and increased disease frequency has been reported. Her data
suggest that DR4 and DR5 are associated with an increased risk
of developing CFIDS/ME/CFS and that it may be triggered in such
people by various stimuli, resulting in a state of chronic
immune dysequilibrium. This would easily explain the findings
with regard to acute viral infections, chronic active viral
infections and allergies in these patients.
In an article titled “Dancing
with the serpent”, Tara Allan wrote: “It’s hard to believe
that people are still so uninformed about the severity of this
illness, but it’s true”. When someone challenged her by
telling her “If you believe, you can get well”, she dared
that person to walk a mile in her shoes before he could tell her
how to live, saying: “In the end, each person copes to the
best of his or her own ability. No-one has the right to make
you or me defend the fact that we are ill. That is completely
unacceptable and incredibly cruel”.
1994:
The Summer issue of
CFIDS Chronicle carried an important article by Professor Paul
Cheney explaining exactly why the 2’-5’ A / RNase L pathway is
so important in (ME) CFS: noting the clinical impression that
patients suffer from a chronic viral infection, Cheney stated:
“Perhaps the strongest evidence that (ME)CFS may be due to
a persistent viral infection is the strong activation in (ME)CFS
patients of a principal anti-viral pathway. The 2’-5’ A
synthetase/RNase L pathway is the most important intracellular
antiviral defence mechanism in mammalian cells….It is initiated
by alpha interferon expressed by activated T cells.
“The alpha interferon binds to
receptors on the surface membranes of most cells in the body.
This receptor binding results in the expression and activation
of 2’-5’ A synthetase, which converts ATP (a source of energy)
to bio-active 2’-5’-oligoadenylates (2’-5’ A). Ultimately, this
pathway activates RNase L…to degrade human and viral
single-stranded RNA.
“Significant activation of RNase
L would substantially disrupt cell metabolism and energy
production and beyond that, organ and body function.
“Hormonal action in the body
would also be substantially disrupted by activation of RNase L.
A clinical situation could arise in which patients appear to be
hypothyroid or hypocortisolaemic, based on clinical signs and
symptoms, even though their actual hormone levels were normal.
“Disruption of messenger RNA by
RNase L would, in effect, functionally decapitate hormone
function at the cellular level.
“This problem would not
necessarily respond to hormone therapy, even if the patient
clearly had clinical evidence of hypocortisolaemia or
hypothyroidism.
“Additional cell functions could
be affected including the production of neurotransmitters within
the brain, detoxification enzymes within the liver and digestive
enzymes within the GI tract.
“In other words, there would be a
‘brown-out’ of organ function and body systems. The action of
RNase L could explain the myriad organ system problems seen in
(ME)CFS and could well be the cause of the severe and
debilitating fatigue in this disorder.
“Alpha interferon, in addition to
activating the 2’-5’ A / RNase L pathway, could cause specific
injury to …the brain. Alpha interferon is known to be a potent
neurotoxin acting though the
m-opioid
receptor in the brain to provoke specific neurotoxic injury to
deep brain structures.
“Alpha interferon injected into
rat brains is known to specifically injure the HPA axis with a
resulting decline in corticotropin-releasing hormone (CRH)
production. A decline in the HPA axis has been demonstrated in
(ME)CFS patients.
Alpha interferon can cause
extensive deep brain injury and may be the common denominator in
explaining why (ME)CFS and AIDS dementia complexes show almost
identical injury to deep brain structures.
“In summary, the alpha
intereferon/2’-5’A/RNase L pathway, if upregulated, would cause
two problems which are ubiquitous to patients with (ME)CFS:
substantial cellular metabolic dysfunction with profound
fatigue; and severe neurocognitive problems due to deep brain
injury.
“At this time, activation
of the alpha interferon / 2’-5’ A / RNase L pathway is the best
common denominator to explain why people with (ME)CFS are sick”.
The seminal work of Professor
Robert Suhadolnik et al on the RNase L pathway was
comprehensively ignored by Wessely School.
In the “Letters to the Editor”
section this same issue of the CFIDS Chronicle, Eileen Marshall
and Margaret Williams responded to Dr Simon Wessely’s reply to
their article published in the previous (Spring 1994) issue
entitled “The Views of Dr Simon Wessely on ME: Scientific
Misconduct in the Selection and Presentation of the Available
Evidence?”
In his reply, Wessely had made
claims which, they pointed out, could not be substantiated;
furthermore, he had admitted that he does not recognise ME/CFIDS
as a distinct entity but includes all people with unexplained
chronic fatigue under the label “CFS”, therefore it is not known
how many of his supposedly cured patients actually had ME as
distinct from chronic fatigue. Marshall and Williams wrote: “It
is sadly true (and we believe it can be readily demonstrated)
that Dr Wessely has indeed changed the facts about ME, that he
has indeed misrepresented the valid findings of other ME
researchers and that he does ignore important findings which do
not support his own views. Bearing this in mind, we feel
justified in querying whether or not this amounts to scientific
misconduct”.
Another published letter on the
same topic was sent by Richard Sykes, then the Director of
Westcare (a small charity that later became subsumed into Action
for ME), defending Wessely and asking for the CFIDS Chronicle to
print an apology to him for having published the Marshall and
Williams article and stating “Failure to achieve balanced
views is not a crime, nor does it imply professional misconduct”.
The editors’ published reply to Sykes was notable: “We
believe that the authors of this article made articulate
arguments when drawing their conclusions. You maintain that
one-sided views are common and acceptable in science and
medicine and, in so doing, you seem to miss the authors’ point.
How has Dr Wessely reached his ‘one-sided view’? With an open
mind, honest investigation and authentic use of the scientific
method? The authors contend not. And, if they are correct, he
may indeed be guilty of scientific misconduct”.
1994:
the Fall issue of the
CFIDS Chronicle published questions and answers in the section
“Ask the Doctor”. One such was the reply provided by Professor
Anthony Komaroff from Harvard, who is also Chief of the General
Medicine Division at Brigham & Women’s Hospital, Boston, as well
as leading a research team for one of the three NIH-funded CFS
Co-operative Research Centres. In reply to the question “Why
do (ME)CFS patients tend to relapse after exercise?”,
Komaroff was clear: “this is due to an unusual reaction of
the immune system to exercise”. He went on to
explain that: “Research groups around the world continue to
report that the (ME)CFS patient’s immune system seems to be in a
chronically stimulated state, as if it is engaged in a battle
against something it perceives as foreign to the body. Even
though the immune system is often in a chronically-stimulated
state, some parts of the system seem not to be working very well
--- perhaps because they have been working too hard”. In
reply to the question “Is there any evidence that (ME)CFS is
caused by an infectious agent?”, Komaroff stated: “In my
judgment, the leading candidates continue to be enteroviruses,
herpesviruses…and retroviruses”.
In an article titled “Immune Dysfunction
in CFIDS: Why You Feel the Way You Do”, Dr Robert Keller from
the Centre for Special Immunology, Miami, explained: “Most
chronic states of immune dysfunction have, as a necessary
requisite, a genetic component. This genetic ‘failing’ occurs
in a region known as immune response genes, or the HLA system….recent
evidence suggests that CFIDS shares this genetic quirk with
other chronic immune activation disorders such as systemic lupus
erythematosus (and) chronic active hepatitis.
“Whatever the nature of the
trigger….in CFIDS, as in all states of chronic immune
activation, the initial presentation of the insulting agent to
the cells of the immune system precludes its initial destruction
or its effective control. As a result…the immune system remains
unbalanced as it tries, albeit unsuccessfully, to rid the body
of the insulting agent. A major consequence of this
unbalanced condition is the persistent production of powerful
cytokines. At some point, this continuous production exceeds
the ability of the body to inactivate them. This, in turn,
results in their systemic dissemination and a variety of
unpleasant consequences….The ability of these cytokines to
interact with receptors that are involved in central nervous
system control creates many other untoward results. It is
now recognised that the brain, the endocrine system and the
immune system represent an inextricably linked triad. Imbalance
in any one of these ‘linked’ systems, therefore, will result in
obligatory disturbances of the other two”.
1994: A four-day
International Research and Clinical Conference co-sponsored by
the American Association for Chronic Fatigue Syndrome (AACFS)
was held in Ft Lauderdale, Florida, on 7th – 10th
October 1994; it was also sponsored by the NIH, the CDC and the
University of Miami. It was reported in the UK ME Associations’
magazine “Perspectives” in March 1995 and in the CFIDS Chronicle
in January 1995 (from which some of these comments are taken
with grateful acknowledgement).
Of the 475 conference participants,
nearly half were clinicians and researchers.
The key-note speech was given by Dr
Philip Lee, then US Assistant Secretary for Health, who spoke of
his recognition of the problems caused by (ME)CFS and of the
need for partnership between governments, researchers,
clinicians and patient groups: “The result is a shared vision
in which science is influenced -- rightfully so – by clinical
experience and patients viewpoint”. Sadly, such
collaboration still does not exist 17 years later, especially in
the UK.
The Conference was in two parts, these
being the research section held on 7th – 9th
October 1994 and the clinical section held on 9th and
10th October 1994.
Knowledge about ME/CFS that was
available in 1994 includes the following:
Dr James Jones of Denver,
Colorado, reported on exercise capacity testing and the
finding of reduced exercise capacity, including abnormal muscle
strength and higher than expected heart rate, as well as high
lactate levels in (ME)CFS patients.
Dr J Vercoulen from Nijmegen
found that patients with (ME)CFS had significantly lower
levels of physical activity then healthy controls and that these
were similar to patients with MS.
Dr Alison Mawle from the CDC
reported that patients with (ME)CFS suffer from higher rates
of allergy-related symptoms than normal controls and these were
present in 70% of patients investigated.
Dr Adrienne Bennett from Brigham
& Women’s Hospital, Boston, measured transforming growth factor
beta (TGFb) and found
that it was elevated in (ME)CFS patients, which might reflect
the body’s attempt to down-regulate an over-active immune
system.
Dr Roberto Patarca (an
immunologist from the University of Miami) pointed out that
there was growing consensus that many of the viruses observed in
(ME)CFS may not be relevant to the aetiology but nonetheless
relevant to the pathology that is seen. He proposed that the
research community start redefining the CDC criteria for (ME)CFS.
Dr Richard Lanham of the State
University of New York at Buffalo reported a very high
frequency (stated as 100%) of eye complaints amongst (ME)CFS
patients studied. Post-onset symptoms included
photosensitivity; photophobia; sensation of foreign body in the
eye; blurry vision; abnormalities of peripheral vision; trouble
reading; ocular pain; headache; floaters; double vision;
itchiness and hazy vision (some of which could be due to fatigue
of the eye muscles). Problems seen on ophthalmic examination
included narrowed arterioles; retinal defect; fibrillar changes
in the vitreous; peripheral cystoid degeneration; drusen;
pigment changes; chorioretinal macular abnormalities; pavestone
degeneration and optic pallor (this being indicative of
neurological disease). Examination of the patients found that
38% had abnormalities of the fundus; 50% had inflamed eyelids
and 41% had other pathologies.
Dr Lanham also reported that a
significantly greater number of patients than controls had a
family member with an autoimmune disease (65% versus 21% of
controls).
He further reported that (ME)CFS
patients have stiff RBC (red blood cell) membranes like those
seen in end-stage renal disease patients, and that this may
represent a unique marker for (ME)CFS: “(ME)CFS patients’
stiff RBCs ‘may not traverse nutrient capillaries well,
resulting in cellular hypoxia…this defect may be part of a more
extensive membrane abnormality’ which may affect neurons and
other cells, leading to additional symptoms” (it is notable
that there is now clear evidence of disrupted biology at cell
membrane level and of abnormal vascular biology, with disrupted
endothelial function in both large and small arteries, pointing
to increased cardiovascular risk for people with ME/CFS – Int J
Cardiol 2011:doi:10.1016/j.ijcard.2011.10.030).
Dr Daniel Clauw from Georgetown
University Medical Centre, Washington, discussed the
relationship between interstitial cystitis (IC) and (ME)CFS: “IC
may be yet another disorder which has considerable clinical and
pathogenic overlap with FM and (ME)CFS”.
In relation to the overlap between the
two disorders fibromyalgia and ME/CFS, Dr Clauw noted the
gastrointestinal symptoms and chest pain frequently described by
patients (hence the need to use accurate diagnostic criteria,
as called for by Dr Patarca).
Dr Lawrence Borish from the
National Jewish Centre for Immunology, Denver, measured TNF-a,
IL-1, IL-6 and IL-10 (all associated with lethargy and
inflammation); they found that TNF-a
and INF-a (interferon
alpha) were increased in ME/CFS patients but decreased in major
depression. Most remarkably, IL-10 was absent in ME/CFS
patients (IL-10 is produced by all T-helper cells and is
stimulated by TNF-a,
the presence of which implies an inflammatory reaction). The
absence of IL-10 supports the characterisation of ME/CFS as an
immune disorder with a defect in the immune system’s ability to
suppress the on-going immune reaction.
Dr Adrienne Bennett from Boston
measured TFG-b (a
suppressor cytokine) in serum from patients with ME/CFS, from
those with depression, with lupus and with healthy controls;
levels were significantly elevated in people with ME/CFS
compared with the other groups. High levels of TGF-b
may be the immune system’s attempt to suppress immune
up-regulation (whilst some parts of the immune system are
down-regulated, others are up-regulated: Dr Joseph Cannon
from Pennsylvania State University provided historical and
scientific evidence that females are more resistant to
infection than males because of an up-regulation of the immune
system; however, it is because of this up-regulation that women
are more susceptible to autoimmune diseases).
Dr Irving Salit from Toronto
General Hospital found that the percentage of CD4 (T-helper
cells) was increased in ME/CFS patient compared with chronically
fatigued controls who did not meet the CDC case definition for
ME/CFS (a finding that is seen in people with allergies). He
determined that ME/CFS patients have “a variety of
immunologic abnormalities (including deviations in)
immunoglobulins, T lymphocyte subsets and cell mediated
immunity”.
Drs Roberto Patarca, Nancy Klimas and
Mary Ann Fletcher et al described three groups of ME/CFS
patients based on patterns of cytokine dysregulation: (1)
dysregulation of TNF-a/b
expression in association with changes in serum levels of IL-1a,
IL-4, (soluble) IL-2R and IL-1 receptor agonist; peripheral
blood mononuclear cell-associated expression of IL-1b,
IL-6 and TNF-b
messenger RNA, and T-cell activation; (2) inter-related and
dsyregulated expression of soluble TNF receptor types 1,
(s)IL-6R and b2-microglobulin,
and significantly decreased lympho-proliferative activity; (3)
significantly decreased NK cell cytotoxic activity.
Dr Kenny De Meirleir from
Brussels studied 149 patients with ME/CFS, categorising
patients’ functional abilities using the Karnofsky Performance
Scale (KS) which scores from 100 (perfectly well) to 0 (dead).
56 ME/CFS patients had a functional ability of less than 65 and
62 scored between 65 and 75. Flow cytometry was used to measure
cellular immune status and the majority of immune abnormalities
were found in the ME/CFS group with KS scores between 65 and
75. The immune abnormalities included increases in
CD3+HLA-DR+ve T cells and an increase in the CD4/CD8 ratio (an
increase in this ratio is found in allergies); there was also a
decrease in NK cells.
It is perhaps worth recalling that at
his Gresham College lecture on 25th January 2006,
Professor Simon Wessely admitted that he does not understand
immunology, something that he had previously admitted on 28th
August 2004 to the Public Inquiry into Gulf War Syndrome,
saying: “A man has got to know his limitations and my
limitations are immunology”.
Dr Dharam Ablashi from Georgetown
School of Medicine, Washington, DC, found that HHV-6 was highly
reactivated in (ME)CFS patients but not in controls. Whilst not
thought to be the cause, HHV-6 seems to contribute to the
symptomatology.
Other researchers present (including Dr
Jan Vercoulen and Dr Gijs Bleijenberg from The Netherlands) were
unable to demonstrate a role for the reactivation of EBV in
(ME)CFS patients.
Dr Daniel Hamilos from the
National Jewish Centre for Immunology, Denver, demonstrated
abnormalities of the autonomic nervous system in (ME)CFS
patients compared with depressed patients and normal controls
and he suggested that this was further evidence for distinct
patho-physiologies in (ME)CFS and depression.
Dr Daniel Clauw from Washington,
DC, looked at inflammatory symptoms of the upper respiratory
tract and bladder, postulating that central nervous system
hyper-activity leads to ‘neurogenic inflammation’, this being an
inflammatory response mediated by the release of neuropeptides
such as Substance P and that this increased level of Substance P
“came from nerves within the bladder and may be responsible
for the irritative symptomatology seen in (ME)CFS and FM”.
Drs Anthony Komaroff and Adrienne Bennet et al concluded,
however, that “despite their clinical similarities, FM and
(ME)CFS are characterised by different abnormalities of the
somatotropic neuroendocrine axis”.
William Pettibon, MA; LMHC from
the Centre for Special immunology, Ft Lauderdale, found that the
results of his neuropsychological study reinforced the view that
(ME)CFS patients were not malingering; together with Dr Nancy
Klimas et al he found specific areas of cognitive
dysfunction, including verbal memory; verbal
attention/concentration; visual attention/concentration; visual
memory; mental flexibility; rate of memory acquisition and in
the level of overall cognitive functioning.
Dr Benjamin Fischler from
Brussels compared SPECT scans of patients with (ME)CFS versus
those with depression and normal controls; cerebral blood flow
was significantly reduced in (ME)CFS patients compared with the
other two groups. Dr Frances Aitchison from Glasgow
presented additional neuroimaging evidence of differences in
blood flow in specific areas of the brain from that which she
had presented in Dublin earlier in the year, this being the
presence of abnormalities not seen in controls, and evidence
that these abnormalities correlated with specific symptom
severity.
Dr Frank Duffy from Harvard
Medical School, Boston, described quantitative
electroencephalogram (qEEG) findings in patients with (ME)CFS
compared with depressed patients and normal controls. Spike
waves were seen in 44% of (ME)CFS patients versus 1.3% of the
other groups, most commonly in the temporal region. (ME)CFS
patients had significantly more sharp waves and frequent bursts
of high amplitude alpha and theta waves in the posterior
regions. Dr Duffy suggested that these abnormalities provide
indirect evidence of an inflammatory process of the central
nervous system, spike and sharp waves being indictations of CNS
irritability. Dr Charles Lapp from Charlotte, North
Carolina, suggested that EEG neurofeedback (phase reversals,
increased slow wave activity, decreased fast wave activity and
an increased amplitude of the brain wave upon cognitive
challenge) could serve as a diagnostic marker for (ME)CFS.
Dr E. Pizzigallo from Chieti,
Italy, carried out muscle biopsies from the vastus lateralis
muscle in (ME)CFS patients and found alterations in the tissue
“compatible with a myopathy of probable mitochondrial origin”,
which might account for the decreased functional capacity
of muscles in (ME)CFS patients. The researchers went on to say:
“even if a mitochondrial damage in the muscles could explain
many aspects of (ME)CFS, we can’t exclude an analogous damage in
the central nervous system to justify the neuropsychological and
neuroendocrinological alterations described in the same
patients”.
Dr James Jones from Denver
reported that maximum oxygen consumption, maximum workload and
anaerobic threshold were reduced in (ME)CFS patients, suggesting
that cardiac function at maximal exercise may be abnormal in
(ME)CFS. He also performed isometric muscle studies in the
quadriceps and hamstring muscles which showed that knee flexor
fatigue, strength and recovery were decreased when compared to
body weight in (ME)CFS patients. He commented that these
dysfunctions may be caused by “deconditioning, intrinsic
cardiac disease or abnormality in the vascular supply or
metabolism of the muscles in the lower extremities”.
Dr J Vercoulen from the
Netherlands compared an assessment of physical activity in 51
(ME)CFS patients, 50 fatigued MS patients and 53 healthy
subjects; (ME)CFS and MS patients scored similarly and
significantly lower than controls on the actometer worn at the
ankle 24 hours daily for two weeks.
(It is interesting to consider why
Professor Peter White decided not to use an actometer as an
accurate measure of activity at the end of the PACE Trial).
Notable short quotes from the question
and answer session of the clinical conference include the
following:
Dr Paul Cheney (in response to
questions about gastrointestinal symptoms in ME/CFS): “Many
of these patients are immune activated and may have leaky guts.
Undigested food protein leaks across the gut and patients
develop reactions to it….CFIDS patients seem to have problems
with detoxification, which may explain their sensitivity to
medications. We are trying to improve liver function to
increase tolerance of medications….Certain vitamins, such as
antioxidants, make very good sense in an immune activated
state….A recent study at The Cheney Clinic demonstrated that
the sickest patients did not respond well to any therapy”.
Dr Anthony Komaroff (responding
to the question: “What causes problems with focusing the eye
in CFIDS?”): “there may be intermittent dysfunction of
the ciliary muscles, which attach to the lens of the eye. If
those muscles are not working well, the lens can’t adequately
change shape and things become blurry”.
Dr Paul Cheney (replying to the
request “Please discuss the neurological aspects of CFIDS”):
“There is evidence of functional neurological injury in
patients with CFIDS as demonstrated by hyper-reflexia, clonus,
balance disturbance and brain irritability”.
Dr James Jones: “I think the
SED rate (the ESR rate in the UK) can be a fooler. There
are a number of individuals who have inflammatory type symptoms,
but their SED rate is absolutely normal. The SED rate is an
old, non-specific test of inflammation which is dependent on
fibrinogen and interleukin-6. But if inflammatory processes are
activated in other ways, the SED rate can be perfectly normal…a
normal or low SED rate does not exclude an inflammatory illness”.
Dr Nancy Klimas (when asked
about the advisability of people with ME/CFS having
flu/hepatitis B or live vaccines): “Personally, I don’t use
live vaccines in any of my patients with immune disorders”.
Dr James Jones added: “There are very few live
vaccines that adults need”.
Dr James Jones (replying to a
question about allergies in ME/CFS: “Is allergy a common
denominator?”): “Clinically, this appears to be so….There
is literature that suggests that allergic patients, when they
get sick, have more symptoms and are sicker longer than other
individuals”.
Dr Anthony Komaroff: “ANA
(antinuclear antibody) tests are abnormal more often”.
Dr Nancy Klimas
(replying to the question “Is there any link between
endometriosis and CFIDS?”): “I see a higher incidence of
endometriosis in my CFIDS patients than in my general clinic
patients” and Dr Anthony Komaroff said: “We have
just done a case-control study…preliminary results indicate that
there may be a higher frequency of endometriosis in the CFIDS
patients versus the controls”.
Dr Sharon Moss: “The type
of cognitive deficits seen in CFIDS patients are similar to
those of aphasia, traumatic brain injury and dementia patients”.
From the Doctor-to-Doctor
session: “The leaders of the session felt that it was
extremely important to validate the patient’s illness”.
The Wessely School profoundly
disagree with such a view: they are on record in 1992 asserting
at the CIBA Foundation Symposium on ME/CFS that the first duty
of the doctor is to avoid legitimisation of ME/CFS patients’
symptoms, a situation that, disturbingly, continues to date in
the UK.
The same issue of CFIDS Chronicle in
which the Ft Lauderdale Conference was reported also carried an
article by Hillary Johnson entitled “A test of Time: Defining
CFIDS in Modern and Historical Terms” in which she quoted from
Dr DA Henderson’s 1956 description of (ME)CFS: “Terrifying
dreams. Crying without provocation. Nausea and headache and
diarrhoea….Back and neck pains. Problems of memory and mentation.
Vertigo. Hyperventilation. Menstrual irregularities. Difficulty
in swallowing. Fatigue. Fast heart…. Paresthesia (transient
numbness and tingling). And paresis (extreme muscle weakness)….
We were left with one possibility. It was also, of course, the
likeliest explanation….It was probably a virus”. In 1959,
Henderson recorded that: “the courses of the patients have
been unaccountably prolonged and debilitating and marked by
frequent exacerbations”. Johnson continued: “Shelokov,
today, is confident that (it), CFIDS and what the English and
Canadians prefer to call myalgic encephalomyelitis are the same
disease: ‘This cannot be…psychiatric, or hysteria, or
hypochondria, or emotional’ ”.
Given what has been known about ME/CFS
for so many years, how is it possible for the Wessely School
psychiatrists who claim to care for such patients to maintain a
fixed position which disregards this body of evidence and to
continue to practise their own psychosocial interventions, the
efficacy of which is not supported by the published data,
including their own?
(To be continued)
click
here for Part II of this article
click here for Part I
)