CONCERNS
ABOUT THE FORTHCOMING UK CHIEF MEDICAL OFFICER’S
REPORT
ON MYALGIC ENCEPHALOMYELITIS (ME) AND CHRONIC
FATIGUE
SYNDROME (CFS), NOTABLY THE INTENTION TO ADVISE
CLINICIANS
THAT ONLY LIMITED INVESTIGATIONS ARE NECESSARY
1st
May 2001
Sally
Montague, Malcolm Hooper
Address for correspondence:
Professor M Hooper
Emeritus Professor of Medicinal Chemistry
Department of Life Sciences
University of Sunderland
SR2 7EE
UK
FOREWORD
I
am happy to be associated with this challenging document written out of the
“white heat” of the suffering and neglect that is so often the lot of people
with ME, 25% of whom are severely affected and wheelchair, house or bed bound.
The need for good science is emphasised throughout the document;
this provides a sound basis for the diagnosis of ME, which is a multi-faceted
condition. These studies need to be
kept in the forefront of the minds of decision makers who are responsible for
advice that will affect the care and management of ME sufferers. It is notable that some of these studies are
supported by funds provided by the UK ME Association (1) and must therefore
have been approved by the Medical Director.
It is essential to address
ME holistically. The
growing body of scientific literature clearly shows that there are profound
disturbances of and damage to the neuro-endocrine-immune systems which must be
understood as inter-connected systems that share many common messenger
molecules.
Functional Medicine
provides an essential paradigm
that identifies the need not only to determine blood or urine levels of
significant marker molecules but also to understand the functional efficiency
of the systems with which they are associated. The paradox of euthyroid levels
of thyroid hormones associated with reduced thyroid function raises difficult
and demanding questions. It is not
enough simply to measure certain parameters.
Such
measurements must be allied to understanding how the whole system is integrated
into the functioning of the whole person. (2)
Overlapping syndromes which share many common symptoms
together with an emerging pattern of biochemical dysfunction (3) are providing
new insights into “syndromes of uncertain origin” which require non-routine
tests for their identification. (4)
These include myalgic encephalomyelitis, chronic fatigue syndrome, Gulf
War Syndrome, Fibromyalgia, Multiple Chemical Sensitivity and pesticide (OP)
poisoning.
Treatment needs to be
prioritised and structured.
This requires a holistic understanding which considers support structures
including the environment, nutrition and nutritional supplements, particularly
as drug therapy in these patients is often precluded by serious adverse
reactions.
References
1. Millennium Medical
Review. ME Association Special Edition, Issue 73. December 1999
2. Rigden S. Functional Medicine Adjunctive Nutritional Support for Chronic Fatigue Syndrome. The Institute for Functional Medicine Inc. PO Box 1729 Gig Harbour WA. USA. (Editorial Board includes Charles Lapp MD)
3. Hooper M IAG: a marker molecule for dietary intervention in Overlapping Syndromes.
J Nutrition Practitioner 2000:2:35-36
4. Syndromes of Uncertain
Origin. Merk Manual Millennium Edition.
Merk & Co Inc. Rahway 1999
Malcolm
Hooper, May 2001
Concerns about the forthcoming UK Chief Medical Officer’s
Report on ME and
CFS, notably the intention to advise clinicians
that only limited
investigations are
necessary
1st May 2001
In
addition to the matters raised in our April 2001 posting entitled Information on Cognitive Behavioural
Therapy, Professor Simon Wessely and PRISMA (www.freealbatross.freehomepage.com), there are further matters of
continuing concern relating to the UK Chief Medical Officer’s forthcoming
Report on ME/CFS which are so important that we believe they should be in the
public domain.
We
are aware that it is quite probable that some members of the Key Group (the “inner circle” of the CMO’s Working
Group on ME/CFS) intend to recommend that the CMO’s Report should advise
clinicians that only limited
investigations are necessary for ME/CFS patients. Our understanding is that this specific advice comes from the
Medical Director of the UK ME Association (Dr Charles Shepherd) and from those
members of the Key Group who are known adherents of the “Wessely School”. Such advice is merely repeating the message
of the 1996 report on CFS of the UK Joint Royal Colleges, which states
unequivocally that no investigations should be done to confirm the diagnosis of
ME/CFS. (1) That Report was
psychiatrically biased (half of the 256
cited references were by the same or associated group of authors, with 10% of
the references being by Professor Simon Wessely himself; nine had not been
published or reviewed); it was deficient
in mention of references to the organic basis of ME/CFS and it was heavily
criticised on both sides of the Atlantic. (2, 3, 4, 5, 6, 7)
We are unable to agree with advice to
clinicians that only limited investigations are necessary or appropriate for
ME/CFS sufferers and believe that such a view is medically and scientifically
untenable; hence we believe there is a legitimate case for making this known in
advance of the Report being issued. In our opinion, it is entirely unacceptable
to advise clinicians that investigations on ME/CFS patients should be limited
to a minimal basic routine screen, especially as basic screening is known to be
often normal in ME/CFS.
In
our view, as Medical Director of the ME Association, Dr Shepherd is supposed to
be representing members of the ME Association and he therefore has an
obligation to represent the best interests of all members of the ME Association
who have to rely on his advocacy.
We
believe that this should involve actively pressing for the setting up of
research units and specialist clinics within the National Health Service for
ME/CFS sufferers, certainly not concurring with the psychiatrists’
recommendation and advising that only limited investigations are necessary for
such patients.
Dr
Shepherd’s own private beliefs are a matter only for him, but at present his
private beliefs seem to be influencing his professional obligations to the
patients he represents and to be adversely affecting decisions which are being
made on behalf of those patients.
We
believe that such advice is at variance with good medical practice and that
assessment of these patients should be particularly thorough; we are not alone
in this view, because US Professors Fred Friedberg and Leonard Jason make the
point in their recent book (8), noting that “Some
physicians make the odd assumption that we know all we need to know about these
illnesses, thus obviating the need for further research and greater
understanding of these patients”.
We
find it difficult to overcome our concern about the fact that the most
influential members of the CMO’s Working Group are all members of
Healthwatch; Healthwatch is funded by
drug companies and in its literature, its clearly-stated aims are to promote
the use of pharmacological interventions and to oppose “Diagnoses…that may encourage unnecessary treatment for non-existent
diseases”. Specifically,
Healthwatch members are opposed to the use of non-pharmacological interventions
such as homoeopathy, acupuncture, dietary modulation or vitamin supplementation
and they are vociferously opposed to all practitioners of alternative or
complementary medicine. Membership of Healthwatch is open only to those who
promote the pharmacological industry (9).
Notably, the Medical Adviser to the UK ME Association (Dr Charles
Shepherd) is a member of Healthwatch, and the involvement of both Professor
Anthony Pinching (Deputy Chair of the CMO’s Working Group) and Professor Simon
Wessely (a very influential member of the Reference Group to the CMO’s Working
Group) has long been known. (9)
Wessely has had connections with Healthwatch since its inception in 1989
(9) and he unceasingly promotes his view that ME is a non-existent disease and
that CFS is a psychiatric disorder which is amenable to antidepressants and
psychotherapy. (For a comprehensive
referenced review of Wessely’s published works on ME / CFS and related subjects
(eg. Gulf War Syndrome), see Denigration by Design? E.Marshall & M Williams. Volume I
(1987-1996) and Volume II (1996-1999), pp 488. Available at cost price from
(UK) 0208-554-3832).
We
believe that investigation is the only way forward towards understanding these
complex disorders and we regret that the CMO’s Report is intending to
amalgamate ME with CFS as a single disorder despite having had it clearly
pointed out that ME and CFS have differing case definitions: by virtue of the current CFS case definitions (Oxford 1991 and CDC
1994), CFS has no physical signs whatever, which is certainly not the case in
ME. Our belief and experience is that
only by looking will we learn.
To
put this important issue in context, we briefly list some of the findings which
were presented at the American Association of Chronic Fatigue Syndrome (AACFS)
Fifth International Research and Clinical Conference held in Seattle in January
2001, which indicate just how essential it is for such patients to be
comprehensively investigated.
Some findings presented
at the AACFS Conference, Seattle, January 2001
It
is perhaps worth reiterating that the American term “CFS” usually reflects
patients who are likely to have ME / “core” CFS rather than psychiatric
disorder as facilitated by the Oxford 1991 CFS case definition (still widely
used by UK psychiatrists of the Wessely School who were participants in its
formulation): this situation is one which requires immediate international
input to end what is obviously a most confusing and unsatisfactory situation
for all involved.
Brain
studies / Neurology
Different
neurobiological profiles are found in CFS patients compared with healthy
controls. Using assays which measured
hormones and cytokines with a potential for affecting the central nervous
system (cortisol, prolactin, oestrogen, progesteron, CRP, neopterin, TNFalpha,
TGFbeta, DHEA-s), significant differences were found in CFS patients compared
with controls. (10)
Both
baseline heart rate and plasma epinephrine were increased in CFS patients,
suggesting an activated sympathoadrenal state. (11)
Sympathetic
nervous system dysfunction is integral to CFS pathology. (12)
A
wealth of studies (about 85%) confirm autonomic nervous system (ANS) dysfunction in up to 90% of CFS patients,
with resulting effects on many vital functions (blood pressure, pulse rate,
breathing and body temperature).
Professor Komaroff said that there is substantial evidence that both the
sympathetic and parasympathetic nervous systems are abnormal in CFS.
CFS
patients showed reduced activation of medial/basal frontal regions but a greater
activation of dorsolateral frontal and temporal lobes than controls. This MRI study showed unique features of
cognitive impairment, demonstrating that more areas of brain activity were used
in task solving than in controls
ie. CFS patients are working
harder than controls to solve the same problem and use more brain areas than
controls. (13)
A quantitative volumetric study suggests that
some CFS patients show a lateral ventricular enlargement, which may be
associated with white matter loss in the frontal as well as the parietal lobes.
(14)
Psychopathology
CFS
patients do not display the same improvement with treatment as seen in
depressed patients. Little overall change is seen in CFS patients on either
physical or mental scores after antidepressant treatment. (15)
Findings
from one of the largest well-studied patient groups in the world which used a
factor analysis (done by computer, which eliminates all bias by the researcher)
suggests that psychiatric disorder is not a core aspect of CFS and that this is
a strong argument against CFS being a psychosomatic or “functional somatic”
disorder. (16)
Whilst
significant neuropsychological impairment was found in CFS patients, no subject
performed in the range suggesting lack of effort or feigned impairment. (17)
The
often-proposed hypothesis that CFS is a form of somatisation disorder was
tested.
It
is apparent that there is no relationship between the number of medically
unexplained symptoms and psychiatric diagnosis. CFS has no relation to
somatisation disorder. (18)
Visual
processing disabilities
Investigation
of the biological basis of visual processing disability in CFS showed that
alteration in visual processing response is associated with evidence of altered
connective tissue turnover. (19)
Biochemistry
Symptom
expression is associated with changes in serum lipid levels. Significant
changes in glucose, amino acid and inflammatory mediating fatty acids may be
involved in
symptom
expression. Increases in levels of polyunsaturated fatty acids had the highest
correlation with both fatigue and muscle pain scores. (20)
Objective
examination of skeletal muscle tissue in CFS patients (biopsy of the vastus
lateralis muscle) showed that activity of all skeletal muscle anti-oxidative
enzymes was significantly increased in CFS patients compared with
controls. Lipid analysis showed fatty
acid modifications in patients but not in controls. Fluorescence polarisation
showed a significant decrease of membrane rigidity with a consequent increase
in membrane fluidity.
There
is evidence of a dengenerative process of the muscle tissue in CFS patients, as
typically occurs in mitochondrial myopathies. This may contribute to muscle
fatiguability and it supports an organic origin for CFS. (21)
Virology
CFS
patients with active HHV6 infection (viraemia) have activation of coagulation
and are hypercoagulable. Since HHV6 is
known to infect endothelial cells, there may be a resultant endothelial cell dysfunction
triggering the coagulation system. (22)
Genetic
abnormalities
Recent
studies have demonstrated circulating plasma RNA in Gulf War Syndrome patients.
A study was therefore conducted to determine the presence or absence of RNA
in CFS patients and to determine if the
amplified sequences of RNA were similar to or
different
from those found in GWS. All chronic
illnesses studied (including GWS, CFS, AIDS and multiple myeloma) show
prominent RNA not observed in normal controls.
Prominent
RNA bands so far sequenced show homology with human genes which are noted for
their tendency for gene rearrangement under severe physiologic stress. The most amplified sequences appear to be
disease specific. (23)
Dr
N.Afari, Associate Director of the University of Washington CFS Research Centre
said that genetic abnormalities may team up with environmental influences to
produce CFS. Environmental influences
which worldwide researchers are investigating include the frequent pairing of
CFS with food and chemical sensitivities. (24)
Microbiology
The
dysregulation of the important anti-viral 2-5 RNase L pathway in CFS is a
potential biomarker for the disorder. The RNase L pathway is a series of enzymatic
reactions which go on inside white blood cells when they perceive themselves to
be challenged by viruses and possibly also by some toxic exposure. Elevated
levels of RNase L are associated with reduced maximal oxygen consumption (VO2max)
and exercise duration in patients with CFS.
Both abnormal RNase L activity and low oxygen consumption were observed
in most patients with CFS. These findings demonstrate that patients’ extremely
low tolerance for physical activity is likely to be linked to abnormal
oxidative metabolism, perhaps resulting from defective interferon responses.
(25)
Much
of the Belgian work focused on the abnormal enzyme pathways found in CFS. In
healthy people, the enzyme breaks down viral RNA and destroys the infected
cell. Instead of the normal size 80kDa (kiloDalton) enzyme, those with CFS show
only a 37 kDa size enzyme. This 37
kDa low molecular weight (LMW) RNase L
fragment found in CFS patients is produced by calpain ( an apoptotic enzyme)
cleavage, and the whole process affects the calcium and potassium channel
mechanisms. The channelopathy will lead to low body potassium. Testing the
ratio of the 37kDa and 80kDa enzymes has revealed that a high ratio is
associated with more severe clinical symptoms.
The 37kDa RNaseL is associated with incomplete cell death, which means
that the cell constituents cannot be recycled for use by other cells. (26)
Patients
suffering from CFS present many symptoms, including pain, which are likely to
reflect dysregulation in cellular ion transport. Fragments released by a
pathological protein cleavage result in dysregulation of sodium channels, which
play a major role in the generation of pain and hyperalgesia in peripheral
neurons, with a resultant shift in the pain sensitivity threshold as well as
causing (if occurring in epithelial cells) drenching sweats. An improper
function of the sulfonylurea receptor (SUR1) could lead to an extreme loss of
cellular potassium. ATP is the main energy releasing source of the cell:
improper function of ATP binding
cassette (ABC) transporters leads to serious neurological dysfunction. Common symptoms of CFS could be due to a
malfunction of various ABC transporters. (27)
Immunology
Increased
apoptosis (programmed cell death) in peripheral blood mononuclear cells (PBMC)
of patients with CFS has been suggested to contribute to the symptomatology.
RNase L activation has been directly linked to the induction of apoptosis. This
study showed that the activation of RNase L in the PBMC of CFS patients
upregulates apoptotic activity in these cells. This suggests that the peturbed
apoptotic process may play a role in the altered immunologic functions in
CFS. (28)
A
large number of CFS patients have an abnormal immunological profile which can
result in the production of immunologic mediators such as interferon,
interleukin and other cytokines. The upregulation of the 2-5A Synthetase /Rnase
L pathway shown in CFS patients indicates an activated immune state. According
to their immunologic profile, CFS patients were divided into three groups. The
results show that the presence of an increased amount of LMW RNase L correlates
with higher levels of interferon gamma. (29)
Autoimmunity
in CFS was reviewed. Low titres of antinuclear antibodies have been found in
CFS patients. A major multi-centre
study looked at the presence of autoantibodies to a cellular protein expressed
primarily in nerve cells ( microtubule-associated protein 2 or MAP2). Initial
studies with immunohistochemistry showed a high percentage of CFS sera reactive
to centrosomes. Preliminary evidence shows that other proteins beside MAP2
might also be target antigens in CFS autoimmunity. Of interest is the high frequency of reactors in lupus and
rheumatoid arthritis as well as in CFS patients. (30)
The
intracellular content of the Natural Killer (NK) cell is perforin, a cell lytic
protein common in many cells of the immune system which correlates with the
cytolytic potential of the cell. In CFS, this chemical is reduced in NK cells.
This finding substantiates claims of an NK associated defect in CFS and suggest
a molecular basis for the reduced cytotoxicity (immune system killer cell
function). This defect may not be NK
specific but may encompass the cytotoxic T cell subset as well. Mice which were genetically engineered to
have low or absent levels of perforin show the same immune abnormalities as
CFS. Other abnormalities found include activated lymphocytes in various
subsets, elevated levels of immunoglobulins (IgG in particular) and increased
levels of immune molecules called pro-inflammatory cytokines. Also found was a
reduced activity of delayed hypersensitivity. (31)
Overlapping
symptomatologies between CFS and Gulf War Syndrome have been observed by
different investigators. It was therefore of great importance to verify whether
various immunologic abnormalities found in CFS are also found in GWS. Overall differences between the two groups
were not significant. The results indicate that, as in the case of CFS, Gulf War
veterans are suffering from neuroimmunological disorder. Importantly, it was shown that basic laboratory
testing is not sufficient for these groups of patients and that advanced
immunological tests including immune function and antibodies to the
neurological system are
needed. (32)
This should be compared with the recommendations in the UK 1996
Joint Royal Colleges’ Report on CFS (1), which specifically state that no
investigations should be performed to confirm the diagnosis (page 45) and that immunological
abnormalities should not “deflect the
clinician from the biopsychosocial approach….and should not focus
attention….towards a search for an
‘organic’ cause” (page 13).
It may also be salutary to
reflect on the opinion expressed by Professor Pinching (deputy Chair of the
CMO’s Working Group) in his article on CFS in Prescribers’ Journal ie. that “over-investigation can (cause patients) to
seek abnormal test results to validate their illness”. (33)
Prescribers’ Journal was a publication of the UK Department of Health
but is no longer produced.
In
our opinion, when taken in consideration of all that is already known about the
biomarkers of ME/CFS, the evidence of serious pathology presented at Seattle
emphasises the unacceptability of advising that such pathology should not be
fully investigated. It also underlines
the fallaciousness of advising that such substantial pathology can be
satisfactorily treated by cognitive behavioural therapy or graded exercise;
thus we believe it is imperative for people to be aware that the most
influential members of the CMO’s Working Group are apparently still determined
to proceed along such avenues despite all the evidence which has been put
before them.
Advice from Members of
the CMO’s Working Group about Testing for RNase L and urinary markers in ME /
CFS
RNase
L in ME/CFS
We
are particularly concerned about the advice which may be issued in the CMO’s
Report that tests for RNase L and tests
for urinary markers should not be performed on UK patients: we understand this is
because the Medical Director of the UK ME Association (Dr Charles Shepherd)
regards them as (quote) “unnecessary and
unproven”. We understand he is further
advising that tests for viral antibody titres are also unnecessary and
unproven.
We
understand that in a forthcoming edition of Perspectives
(the magazine of the UK ME Association), Dr Shepherd intends to inform readers
that his view of the well-conducted international work on RNase L is that it
“ may involve what I and many of
my colleagues regard as over-investigation for highly speculative abnormalities
in antiviral pathway activity”.
We
compare the personal opinion about the significance of RNase L of the Medical
Director of the UK ME Association not only with the evidence demonstrated in the
Seattle presentations outlined above but also with what Professor Anthony
Komaroff wrote about the work on RNase L of De Meirleir et al in an Editorial
in The American Journal of Medicine: “What is this research telling us? It is another piece of evidence that the
immune system is affected in chronic fatigue syndrome and it reproduces and
extends the work of another investigator (Professor Suhadolnik), lending
credibility to the result”. (34)
We further compare Dr Shepherd’s view with that of Shetzline and
Suhadolnik, who in a detailed study of the RNase L enzyme have not only
identified the 37kDa form of the enzyme as being part of the underlying
pathology of ME/CFS, but with
sophisticated labelling techniques have shown that there is an increased rate
of RNA hydrolysis by this enzyme and that the low molecular weight enzyme (37
kDa instead of the normal 80 kDa weight) is hydrolysing three times faster than
the normal 80 kDA enzyme. Significantly, the researchers have used a specific
probe which unequivocally identifies the faulty enzyme. (35)
We
note that those with ME/CFS show both an upregulation of the antiviral pathway
and an abnormal version of the RNase L enzyme
(ie a low molecular weight of 37 kDa); patients who express this
abnormal RNase L enzyme suffer an even greater depletion of ATP reserves and an
inhibition of protein synthesis (ie. when the various protein kinase enzymes
become activated and elevated, protein synthesis is inhibited).
Expression
of this low molecular weight RNase L can cause problems with enzymatic
detoxification pathways, particularly in the liver (see below). Measurements of protein kinase 1 are very
important in studying mechanisms of interference with signal transduction in
lymphocytes, and distinct abnormalities
are seen in ME / CFS.
In
our opinion, for the Medical Director of the UK ME Association to advise that
no RNase L investigations are necessary defies reason. Accumulating evidence (of which the CMO’s
Working Group ought to be aware) dictates that such investigations are
essential if this serious disorder is ever to be understood.
Possibly
of relevance to Dr Shepherd’s advice are the significant findings by Professor
Vojdani and Dr Charles Lapp, namely their discovery that this same antiviral
pathway can be damaged by chemicals. (36)
This work relates to the findings of Dr Howard Urnovitz from the Chronic
Illness Research Foundation at Berkeley, California, whose work has been
published in the Journal of the American Society for Microbiology and in
Clinical Microbiology Reviews; he has demonstrated a fundamental breakthrough
linking toxic exposure with chronic diseases such as ME/CFS and other
autoimmune disorders; (37)
he and others suggest that the huge increase
in chemical usage is chronically stimulating the immune system. Clearly, such findings might be unpalatable
to members of Healthwatch and to the chemical and pharmacological giants whose
interests Healthwatch was set up to serve.
Urinary
markers in ME/CFS
Another
area where we disagree with Dr Shepherd’s advice to the CMO’s Key Group
concerns his recommendation that there should be no investigation of urinary
markers in ME/CFS. We believe several
urinary markers are important and that where certain
markers
are positive, dietary modulation can result in alleviation of distressing
gastro-intestinal symptoms. Given that
the remit of the CMO’s Working Group is to assess treatment and management of
these patients, assessment of something which can deliver any relief should
surely be a priority.
We
make particular mention of just three urinary markers which in our view merit
inclusion in the assessment of patients suspected of having ME/CFS:
(i)
CFSUM1
(Chronic fatigue syndrome urinary marker 1). In February 1995 Dr Neil McGregor of the University of Newcastle
(Australia) CFS research team presented information at a CFS Conference in
Sydney about the nature of the novel chemical which his team had found in the
urine of people with ME/CFS; the urine concentration appeared to correlate
strongly with a number of ME/CFS symptoms.
The chemical name for this marker is
amino-hydroxy-N-methyl-pyrrolidine. The
base structure of this compound is similar to the base structure of many
pesticides. This team went on to
characterise more markers: at the Brussels World Congress in September 1999,
another member of the Newcastle team (Dr Hugh Dunstan) presented evidence of UM
27 (urinary metabolite 27); this marker molecule was elevated in ME/CFS and
there was a positive correlation with elevation and symptomatology.
(ii)
IAG
TESTING (indolylacroylglycine, a tryptophan
metabolite). This is a test for urinary
markers which is almost 100% positive in ME/CFS. It is inexpensive and is
available at a British university. We believe that screening for allergies and
hypersensitivities should be mandatory in these patients, as the cost is
minimal and the benefit is considerable; thus the cost-benefit ratio is
eminently justified. It is our opinion
that specific advice should be given in the CMO’s report about the very real
value of elimination diets in cases of ME/CFS where there is reproducible and
reliable evidence of a leaky gut, in which high levels of small peptides cross
the damaged gut membrane, leading to changes in brain chemistry which have
behavioural, cognitive, neurological, endocrinological and immunological
consequences. The well-validated IAG urine test is a test for an aberrant
metabolite of tryptophan and if positive, is indicative of a malfunctioning and
leaky gut; it indicates a compromised
digestive process which in turn leads to opioid excess as a result of
mal-digestion and uptake of opioid peptides derived from dietary sources. The main culprits are well-known as being
the opioid precursor peptides gluten and casein, with casein from cows milk
causing more problems than casein from sheeps milk; they are broken down in the
gut to opioid peptides, namely gliadomorphin and casomorphin and it is these
which readily cross the damaged gut membrane and give rise to a cascade of
multi-systemic problems. These
“escaped” peptides are scientifically measurable in urinary peptide profiles.
(38) Significantly, if the gut is leaky, the same factors also
cause the blood brain barrier to be
leaky, with resultant effects of opioids on the central nervous system; this
causes not only a local, but also a systemic, reaction. Studies show that this is not a genetic
phenomenon but an acquired one. On this same aspect, we note that Wessely
himself (perhaps the archetype non-investigator) is now recommending that all
ME/CFS patients be routinely screened for undiagnosed coeliac disease,
stating “there is now evidence from primary care of a surprisingly high
frequency of unsuspected EMA tests (endomysial antibodies) in people with non-specific symptoms….we
now suggest that screening for CD (coeliac disease) should be added to the relatively short list of mandatory investigations in cases of
suspected CFS”. (39) Both these factors may relate to the
increased incidence of irritable bowel syndrome in ME/CFS, which is high: 73% as opposed to 22% in the general
population. (40)
(iii) Urinary creatine test
At the British Society of Rheumatologists’ Conference in Edinburgh,
April 2001, evidence was presented which showed that patients with ME/CFS are excreting
in their urine significant levels of creatine and other muscle related
metabolites including choline and glycine.
(53% of ME/CFS patients were positive compared with 0% of healthy
controls). This may well represent evidence of on-going muscle damage in
ME/CFS. Creatine has previously been
shown to be a sensitive marker of muscle inflammation. (41)
From
these illustrations, we believe it may be appropriate for the Medical Director
of the UK ME Association to be required to supply a credible explanation as to
why he recommends that investigation of urinary markers in ME/CFS is
“unnecessary and unproven”.
General observations
Whilst
it is true that there is as yet no single, definitive laboratory test for
ME/CFS, there is a spectrum of abnormalities which, if positive, enable a
diagnosis to be made with reasonable certainty; if minimal routine
investigations are to be carried out on UK sufferers, then no progress will be
made in the medical understanding of ME/CFS and unnecessary suffering will
continue. In our view, that is
unacceptable.
Immunological testing
The
immune abnormalities documented in ME/CFS follow a recongisable, reproducible
and consistent pattern, with clear evidence of an immune activation state. In our view, screening for NK levels and
function per cell (and not
just gross killing) is mandatory, as is measurement of the CD4-CD8 ratio; other
immunological tests should routinely include testing for ANAs (antinuclear
antibodies), IgGs, including IgG3, CICs (circulating immune complexes), IL2;
IL4 (interleukin 2 + 4), measurement of Th1 - Th2 response and mitogen
stimulation tests. In particular, tests should be performed for thyroid
antibodies (see below). It has been
demonstrated that in ME/CFS, changes in different immunological parameters
correlate with particular aspects of disease symptomatology and with measures
of disease severity. (42). Further
consolidation of the correlation between ME/CFS symptomatology and evidence of
immune dysfunction is to be found in the convincing work of Natelson et al who
have demonstrated the link between IL4 and a type 2 cytokine pattern in ME/CFS;
a preponderance of a Th2 response is consistent with autoimmunity. (43, 44).
In particular, we suggest that ME/CFS
patients should be screened for evidence of autoimmunity. There is increasing evidence of antilamin
antibodies in ME/CFS: specifically, antilamin antibodies have been found in the
blood of ME/CFS patients (antibodies
against this protein are proof of autoimmunity and of damage to brain
cells). It has been demonstrated that
52% of patients with ME/CFS develop autoantibodies to components of the nuclear
envelope (NE), suggesting that in addition to the other disturbances of the
immune system, humoral autoimmunity against polypeptides of the NE is a
prominent immune derangement in ME/CFS. The occurrence of autoantibodies to an
intracellular protein like lamin B 1 provides laboratory evidence for an autoimmune component in ME/CFS. No patients with depression or atopy showed
reactivity to NE proteins.
Autoantibodies to NE proteins are relatively infrequent in routine ANA
serology and most of these fall into the broad category of an unusual
connective tissue disease subset which is characterised by brain or skin
vasculitis. (45,46) As mentioned
above, results of a multicentre study looking at autoimmunity in ME/CFS
presented at the AACFS Fifth International Research and Clinical Conference at
Seattle in January 2001 looked at the presence of autoantibodies to a cellular
protein expressed primarily in neuronal cells (MAP2). Immunohistochemistry
results showed a high reactivity in ME/CFS patients, as also in patients
diagnosed with lupus and rheumatoid arthritis. (30) Mindful of the serious and costly consequences (both human and
financial) flowing from undiagnosed AI (autoimmune disease) and bearing in mind
the present body of evidence, we fail to understand the re-emergence in the UK
of advice that such investigations are “unnecessary” and “inappropriate”.
Virological screening
We
again point out the importance of screening for viral antibodies as early in
the diagnostic process as possible: it
is imperative to ascertain any viral trigger but antiviral antibody levels fall
off after three months. It is crucial to look for viral markers because
management interventions must always
refrain from doing harm and the enforcement of unvalidated exercise regimes
upon such patients could, in our opinion, result in indefensible legal action.
There is a body of published, competent medical opinion which supports the
involvement of CBV (Coxsackie B virus) in at least a subgroup of ME/core CFS,
especially those with cardiac, pancreatic and gut dysfunction (47, 48, 49, 50,
51); this being so,
the CMO’s guidelines on ME/CFS management cannot afford to ignore or dismiss
it. We believe that this aspect should
be brought to the specific attention of clinicians.
Endocrine testing
We
also suggest that detailed endocrine function studies be included in the recommendations
to clinicians. The endocrine system is uniquely disrupted in ME/CFS.
(52,53,54) A key feature is the
demonstrated defect in HPA axis function (55, 56) and patients are severely
limited by the loss of dynamic hormone responses. There is an abnormality of adrenal function and CT scans have
shown that both the right and left adrenal glands are reduced by 50% when
compared with controls. (57) In one of
the larger studies, Lucinda Scott MB,
MRCPsych (part of the Scott / Dinan
team of ME researchers) looked at the common neuroendocrine tests (which are
often normal in ME/CFS) and concluded
the tests were inadequate for ME/CFS patients. (58)
Specifically,
we believe that thyroid function needs careful evaluation in ME/CFS: it has
long been noted by practitioners that ME/core CFS patients are often clinically
hypothyroid even though biochemically euthyroid. Evidence suggests that such
patients may not really be euthyroid, especially at the tissue level. (59) Abnormal thyroid hormone levels have been
described in autoimmune disease. (60)
In our opinion, particular attention needs to be paid to investigating
the bioavailablity of T3. In ME/core
CFS, T3 levels are often low (or at the low end of the normal range). We therefore suggest that selenium levels be
investigated in patients with ME/core CFS who have reduced T3 levels: this is because selenium (as selenocysteine)
is an integral component of two important enzymes, glutathione peroxidase and
iodothryonine deiodinase; it is
expressed in the liver and it regulates the conversion of thyroxine (T4) to the
active and more potent T3. Individuals
who have a deficiency of 5’ deiodinase cannot produce T3 from T4 (61),
thus it is advisable to establish baseline levels of selenium in ME/CFS
patients whose T3 levels are low. Additionally, recent evidence demonstrates a
lymphoctyic thyroiditis in chronic fatigue. (62)
Central, autonomic and
peripheral nervous system testing
There
is a universally acknowledged dysfunction of all nervous systems in ME/core
CFS. (63) Testing for Rombergism and
nystagmus is mandatory in ME/CFS but often overlooked. Nystagmus is jelly-like
and variable: a patient examined in the morning might have nystagmus, which
would disappear at midday, recur later, disappear and recur the next day (64);
thus a once-only cursory examination could be misleading.
Given
what is now known, we believe that tests for sympathetic over-activity and for
orthostatic hypotension in ME/CFS should not be omitted. (65)
Nuclear imaging
There
is objective evidence of brain impairment in the majority of patients with
ME/CFS
(66,
67, 68, 69); such patients show a particular pattern of hypoperfusion of the
brain stem and this brain perfusion impairment provides objective evidence of
central nervous system dysfunction. Brain magnetic resonance imaging (MRI) data
have demonstrated that the presence of brain abnormalities in ME/CFS are
significantly related to subjective reports of physical function ie. ME/CFS patients with MRI brain
abnormalities are more physically impaired than those without MRI brain
abnormalities. (70)
Tests for
hypercoagulability and vascular dysfunction
There
is increasing evidence of hypercoagulability in ME/CFS. Researchers in Phoenix, Arizona have
demonstrated a model of coagulation activation in ME/CFS; using five tests
(
fibrinogen, prothrombin fragment 1+2, thrombin / anti-thrombin complexes,
soluble fibrin monomer and platelet activation by flow cytometry), they have
shown that ME/CFS can be classified as a type of antiphospholipid antibody
syndrome. (71) Phospholipids are
constituents of all tissues and organs, especially the brain; they are
synthesised in the liver and small intestine and are involved in many of the
body’s metabolic processes. An antiphospholipid antibody syndrome is a clinical
disorder with recurrent arterial and venous thrombotic events; the heart,
central nervous system and skin may be affected. This is significant because in
ME/CFS, vascular problems are well-documented: at the World Congress on ME/CFS
in Brussels 1999, it was stated that vasculitic patterns are identical to those
in HIV patients. (72) Scientists in
Dundee, Scotland have demonstrated the presence of a defect in peripheral
cholinergic activity within the vascular endothelium; this abnormality
affecting the blood vessels may provide an explanation for some of the vascular
features seen in ME/CFS. (73) In
addition, increased sensitivity to glucocorticoids in peripheral blood
mononuclear cells has been demonstrated (74), which is important evidence of a
biological marker in ME/CFS.
Lung function testing
Tests
have shown that compared with controls, patients with ME/CFS showed a
significant reduction in all lung function parameters. (75) There is repeated reference to respiratory
problems throughout the ME/CFS related literature. (76, 77)
Tests of exercise
capacity
Investigation of exercise capacity (VO2
max) ie. measurement of maximal oxygen uptake
and investigation of oxygen delivery to muscle are essential in patients
with ME/CFS; oxidative metabolism is known to be reduced in ME/CFS. (78) This could affect patients’ physical
abilities to a severe degree. ME/CFS
patients have recovery rates for oxygen saturation that are 60% lower than
normal controls. (79) It is imperative to
ascertain oxygen delivery status before insisting on inappropriate
interventions eg. CBT / graded
exercise.
Tests for cardiac
anomalies
Cardiac
anomalies are well-documented in the ME literature. (80, 81, 82) In our opinion, such anomalies should always
be looked for in ME/CFS patients.
Tests for liver
dysfunction
Given
the evidence of hepatic dysfunction in ME/CFS, we suggest that liver
involvement should always be assessed. (83, 84, 85). In our experience, this
rarely happens.
Ocular tests
Ocular
problems are common in ME/CFS (86,
87,88) and we believe ocular testing should be carried out on ME/CFS patients.
Conclusion
We
acknowledge that this summary discusses international research findings which
have been carried out in centres of excellence, and that it is unrealistic to
expect all tests mentioned to be readily available at all hospitals throughout
the country. Nevertheless, we believe
that the need for specialist ME/CFS units (providing both complex investigative
and assessment facilities, together with the necessary care provision) are long
overdue, and that advice contained in the forthcoming CMO’s Report should
reflect this need.
This
summary is merely an outline of just some of the abnormalities which are known
to be present in ME/CFS; it is by no means a comprehensive list (for example,
it does not include reference to neuropsychological assessment in ME/CFS
patients, which is known to produce a distinctive pattern of abnormalities).
It
is hoped that it might serve to motivate people into contacting their Member of
Parliament, their legal advisers and the media about the continuing exclusion
of patients with ME/CFS from NHS provision and delivery of care as at present,
and about the apparent determination of some members of the CMO’s Key Group to
advise in the forthcoming Chief Medical Officer’s Report on CFS/ME that for
such patients, “only a limited set of
investigations are necessary”.
Given the extent of the evidence of such complex underlying patholology,
we believe such advice is indefensible.
Finally,
we again draw attention to the factual evidence set out in our observations on
claims by psychiatrists of the Wessely School that CBT is the evidence-based
treatment of choice for ME/CFS (Information on Cognitive Behaviour Therapy,
Professor Simon Wessely and PRISMA, April 2001,
www.freealbatross.freehomepage.com) and in this respect we would draw
attention to the mounting evidence that cognitive behavioural therapy has been
shown to be of no long-term benefit in disorders other than ME/CFS:
in
a multi-centre study, researchers from the Department of Psychiatry and
Behavioural Sciences at The Royal Free and University College Medical School,
London, have found that there are no differences in clinical outcomes between
cognitive behavioural therapy and the usual general practitioner care at 12
month follow-up for patients suffering from depression and from depression with
co-existing anxiety. (89). Members of the CMO’s Working Group may wish to take
note.
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