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CO-CURE Medical & Research Posts Only Digest - 27 Nov 2006 to 2 Dec 2006 (#2006-54)
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Date:    Tue, 28 Nov 2006 11:28:25 -0500
From:    "Dr. Marc-Alexander Fluks <fluks@xxx.xx>" (via Co Cure Moderators)
Subject: RES,NOT: CFS Science Classification System: determine scientific, value of CFS research

Think like a scientist, act like your doctor: you can now determine
the scientific value of CFS research yourself.

Surf to,

The classification process is simple: determine which characteristic
topics are present in a CFS research project, find the corresponding
number of points, add the numbers and then find the scientific value
of a research project.

It is the first version - so please send your comments to <me-net@dds.nl>
for future updates.

[Return to top]            


Date:    Tue, 28 Nov 2006 11:32:40 -0500
From:    "Blake Graham <blanket@xxx.xxx.xx>" [via Co-Cure Moderators]
Subject: MED:Correcting disordered sleep in CFS

Dear Co-Cure readers,

I have recently written a detailed (3000+ words) article on treating sleep disorders in CFS patients. It is available online at:

Best regards,

Blake Graham, B.Sc (Honours)
Clinical Nutritionist

[Return to top]


Date:    Tue, 28 Nov 2006 11:25:31 -0000
From:    Stephen Ralph <stephen.e.ralph@xxxxx.xxx>
Subject: ACT,NOT,RES: Digest of Gibson Report on CFS/ME - By Horace Reid

Permission to Repost


Digest of Gibson Report on CFS/ME.

Horace Reid.

On 26th November an all-party group of parliamentarians launched an
explosive report on the lack of British research into CFS/ME. They said:

·        Although there is no compelling evidence that CFS/ME is
psychological, there is persistent psychiatric bias in the UK.
·        The UK is lagging in biological research; important international
research is ignored.
·        The Medical Research Council is funding only psychological research
into CFS/ME.
·        The ME patient community is "extremely hostile" to certain
·        Current treatments amount only to symptom management, not cure.
·        There should be a government inquiry into ongoing research failure.
·        Some senior doctors have a "blatant conflict of interest", and
should be investigated.

The group was chaired by Dr. Ian Gibson, past chairman of the Commons
Science and Technology Select Committee. Other members included veteran
Labour MPs Ann Cryer and Michael Meacher, Dr. Des Turner, chairman of the
All Party Parliamentary Group on ME, Lords deputy Speaker the Countess of
Mar, and Lord Turnberg former President of the Royal College of Physicians.

£3.5 Billion Annual Cost.

CFS/ME is one of the most contentious illnesses in modern medicine, say the
MPs. In Britain it affects more than 200,000 patients. It can be a severely
incapacitating illness; many who suffer from it have their lives completely
ruined. There is no effective method of diagnosis, treatment or cure.
Current NHS provision leaves much to be desired. CFS/ME costs the UK about
£3.5b annually in medical services, social benefits and lost incomes.

Some Doctors Stigmatize ME Patients.

The MPs say they "heard a number of extremely disturbing testimonials from
patients dismissed by their GPs as 'attention seeking'." The inability of
some in the medical profession to identify genuine patients with CFS/ME
"enhances the view that all patients with CFS/ME are neurotic or not
genuinely ill".

They were also "concerned to receive written submissions from parents of
children with CFS/ME " who were disbelieved by social services and GPs. As a
result "their children were put on the at risk register, or even made wards
of court and removed from the family home." The MPs said CFS/ME "should not
be confused with Munchausen by Proxy".

Psychiatric Bias.

ME and CFS have been defined as neurological illnesses by the World Health
Organisation. "There is no compelling evidence it is purely psychosocial",
say the MPs. But in Britain there has been a clear historical bias towards
research into the psychosocial explanations of CFS/ME, they found. "The UK
has not been a major player in the global progress of biomedical research
into CFS/ME".

The effects of this psychiatric bias can be seen in some major British
textbooks for doctors. The 2004 edition of Kumar & Clark's "Clinical
Medicine" relegated CFS/ME to the chapter on psychiatric medicine. "While
CFS/ME remains only in the Psychological section of medical discourse, there
can be little chance of progress", the MPs conclude.

Professor Wessely of King's College Hospital is considered by many to be the
leading expert on treating CFS/ME. But many patient groups believe Dr.
Wessely and his colleagues are responsible for the perception that ME is a
psychosocial illness. "It is clear the CFS/ME community is extremely hostile
to the psychiatrists involved". "The Group invited Wesseley to speak at an
Oral Hearing, however he declined the offer", says the report. "The Group
were disappointed not to have the opportunity to discuss this important
issue with such a key figure".

No medical witness who appeared at the Oral Hearings proposed that CFS/ME
was entirely psychosocial. "So why has this model taken such a prominent
role in the UK?" the committee asked.

International Research Ignored.

The committee preferred the Canadian diagnostic protocol to existing British
criteria, and reproduced it in full in their report. "The Canadian Clinical
Criteria were much more detailed, including many more symptoms of CFS/ME
compared with the Oxford Criteria". They also admired new American
guidelines issued by the US Centers for Disease Control: "The CDC provides
very patient focused criteria".

The MPs wondered why British doctors had not made use of valuable
international research: "The Group was very interested in the international
evidence submitted and concerned as to why this evidence has not been
seriously examined in the UK".

Biomedical research needed.

"The underlying theme in all of our hearings was the paucity of research
into causes", said the Group. The origins and causes of CFS/ME will only be
found through scientific research. Provision of resources for biomedical
research is urgently needed. But there has been no massive investment.
Research areas defined by the Chief Medical Officer's 2002 Report on CFS/ME
have not been addressed.

The MPs called for a government Inquiry into the Scientific Evidence for
ME/CFS, undertaken by independent scientific and medical experts, (including
virologists, immunologists, biochemists) to objectively assess the relevance
of international scientific data.

They called for a crash programme of research investment, similar to the
AIDS project funded previously by the MRC.


Existing treatments consist of psychotherapy and exercise (CBT & GET). These
treatments "should be regarded as symptomatic treatments, not as cures", say
the MPs. CBT is at best only a partial answer. "It is most effective in
those with less severe forms of CFS/ME and appears to be much less effective
in those with severe disease".

"GET is an area for particular concern", they continued. "Some of our
evidence suggests that GET carries some risk". Some patients claim they are
harmed by this treatment, and as a result, there can be "serious antipathy
to the doctors offering it", the MPs found.

Treatment guidelines for CFS/ME will be released by the National Institute
for Clinical Excellence next April, and will likely recommend CBT and GET.
"The Group is concerned that NICE guidelines are recommending these
treatments without caveats", says the report. NICE guidelines should accept
that, as the causes and pathogenesis of ME/CFS remain poorly researched,
treatments are empirical and of only marginal symptomatic help in some
cases. "NICE will certainly benefit from listening to international
experts", they say.

Depression caused by medical neglect.

The committee noted a "close link with depression in many ME cases." However
many cases of depression were made worse by medical neglect.  There are
"professionals who do not believe" CFS/ME patients, and subject them to
"social stigma." Often CFS/ME is not accepted as a legitimate condition;
there is "lack of classification". Unlike other illnesses, there is less
"possibility of a cure." All of these factors "leave the CFS/ME sufferer
more disillusioned than those with other chronically disabling diseases, and
thus more prone to depression".

MRC Bias.

The Medical Research Council confirmed that from Apr. 2003 to Nov. 2006, it
has turned down 10 biomedical applications relating to ME/CFS. Over the same
period it has funded five applications relating to CFS/ME, mostly in the
psychiatric/psychosocial domain. These amounted to £11m. Biomedical
applications rejected include those by Professor Jill Belch (herself a
Principal Fellow of the MRC) and Dr Vance Spence of Dundee, as well as Dr
Jonathan Kerr of St Georges, London.

"The group were concerned by the MRC CFS/ME Research Advisory Group paper",
which concentrated "research effort on case management and 'potential
interventions' ", and "diverted attention away from the need for more
research into causation and diagnosis". "The MRC should be more open-minded
in their evaluation of proposals for biomedical research into CFS/ME". "They
should assign at least an equivalent amount of funding (£11 million) to
biomedical research as they have done to psychosocial research".

Social Security Benefits.

People with ME/CFS, like others, often experience great difficulty in
obtaining state sickness and disability benefits. CFS/ME patients are at a
massive disadvantage because of the controversy surrounding the cause of
their illness and suggestion that it may be psychosomatic. At present ME/CFS
is defined as a psychosocial illness by the Department for Work and Pensions
(DWP) and medical insurance companies. This classification is in the
financial interest of both the DWP and the insurance companies.

"The sooner there is a biomedical model of assessment for this illness the
better", say the MPs.

"The Group feels that patients with CFS/ ME, which is often an extremely
long term condition, should be entitled to the higher rate DLA. Until
medical opinion is better informed as to the nature of this illness ME
sufferers will have to live with the double burden of fighting for their
health and their benefits".

"Blatant" Medical Conflict of Interest.

"There have been numerous cases where advisors to the DWP have also had
consultancy roles in medical insurance companies. Given the vested interest
private medical insurance companies have in ensuring CFS/ME remain
classified as a psychosocial illnesses, there is blatant conflict of
interest here. The Group find this to be an area for serious concern and
recommends a full investigation of this possibility by the appropriate
standards body".


The MPs say they will not be "distracted by debates centring on semantics in
this difficult and contentious field. The principal actuality remains, that
there exists a serious disease, which causes much suffering for patients,
and which may be severe and incapacitating."

"Our aim is to build consensus from this point forward', and to "ensure that
the voice of the patient is heard".

[Return to top]


Date:    Tue, 28 Nov 2006 16:15:54 +0100
From:    Jan van Roijen <j.van.roijen@xxxxx.xxx>
Subject: act,med: MERUK NICE Stakeholder Comments


Send an Email for free membership
       >>>> Help ME Circle  <<<<
 >>>> 28 November 2006     <<<<
Editorship : j.van.roijen@xxxxx.xx
Outgoing mail scanned by Norton AV

From:  "Neil Abbot" <Neil.Abbot@xxxxx.xxx.xx>

National Institute for Health and Clinical Excellence
Stakeholder Comments; 23rd November 2006

Organisation: ME Research UK

Address: The Gateway, North Methven St, Perth PH1 5PP, UK;

Author of comments: Dr Neil Abbot, Director of Operations

The draft produced by the Guideline Development Group (GDG)
is unsafe and unsatisfactory ("unfit for purpose") because it does
not engage with key issues involved in the diagnosis and
management of ME/CFS. These comments briefly outline the
areas where core difficulties arise, and then present a line-by-
line critique of the main limitations. These core areas of difficulty
can be divided into the following:

1. The problem of the diagnostic rubric and the need for
research-based subsets.

2. The skewing of the RCT evidence-base examined by the
GDG, and the devaluation of evidence from scientific studies
and surveys. 3. The limitations of the evidence base for
non-specific management and coping strategies.


1. Problem of diagnosis and the need for research-based

As the draft guidelines point out, ME/CFS is a diagnosis of
exclusion based on a collection of vaguely defined symptoms
that it shares with other illnesses. While the GDG has tried in
good faith to fulfill its remit – to suggest guidelines for "diagnosis
and management" – it has failed to ask what the diagnosis"
means and which patients or groups of patients it contains.
Without addressing these issues, the guidance is no more than
the blind leading the blind round in circles.

Terminology is the 'hot' issue in ME/CFS: it energises the
debate between patients and healthcare professionals, and it
impacts on patient management, clinical practice, and the
results of clinical trials (which are heavily dependent on the
entrance criteria used to recruit subjects). The issue can be
simply put. The original case description of the illness, myalgic
encephalomyelitis (ME) - Acheson, 1959; Dowsett et al, 1990 -
referred to a condition, commonly of infectious onset,
characterised by:

a) Exercise-induced myalgia and fatigue precipitated by trivial
exertion (physical or mental).`

b) Neurological disturbance, especially of cognitive, autonomic,
and sensory systems. This could include impairment of
short-term memory and loss of powers of concentration, usually
coupled with emotional lability, nominal dysphasia, disturbed
sleep patterns, dysequilibrium and/or tinnitus.

c) An extended and relapsing course with fluctuation of
symptoms, usually precipitated by either physical or mental
exercise; typically, the symptoms vary capriciously from
hour-to-hour and day-to-day with varying involvement of the
cardiac, gastro-intestinal, and lymphoid systems.

Since the late 1980s, however, the medical profession has been
urged by a small subset of its members to adopt the term
Chronic Fatigue Syndrome (CFS), a more wide-ranging
diagnostic category which includes patients whose dominant
symptom is medically unexplained, on-going, or chronic fatigue
(in conjunction with several other physical or psychological
symptoms) who would not necessarily fulfil the original criteria for

There are now several definitions of CFS, all still unvalidated in
2006; the Guideline Development Group (GDG) has mentioned
these (FULL Guideline, page 111- 2), but has not grasped their
significance. In the USA, the 1994 CDC case- definition of CFS
is currently utilised (Fukuda et al, 1994), supplanting its
predecessor, the 1988 CDC criteria. However, in the UK, a
frequently-used case definition is the 'Oxford criteria' (Sharpe
1991) which can include patients with no physical signs and
inadvertently selects subgroups of patients with high levels of
psychological diagnoses (Katon & Russo 1992; Freiberg 1999).
Since the adoption of a particular case-definition of CFS will
greatly influence the outcome of particular studies, it is perhaps
no surprise that groups researching biopsychosocial
management and coping strategies have tended to use the
broader Oxford criteria, whereas groups outside the UK (mainly
in the USA) have tended to use the Fukuda et al 1994 definition
for their biomedical research.

Today – whichever definition is used – the term ME/CFS (or
CFS/ME which the GDG prefers) is an impossibly wide
"umbrella term", based on a collection of vague non-specific
symptoms shared with other illnesses, that contains different
patient groups. The issues surrounding the establishment of
CFS as a diagnostic category, and the inaccurate and biased
characterisations of CFS that have subsequently arisen, were
well-reviewed a decade ago by Jason et al (1997), and their key
points are still valid:

...A significant complicating factor in understanding the
dynamics of this illness is that there are probably different types
of illnesses now contained within the CFS construct... We
believe that it is crucial for CFS research to move beyond fuzzy
recapitulations of the neurasthenia concept and clearly delineate
precise criteria for diagnosing pure CFS and CFS that is
comorbid with psychiatric disorders. It is also necessary to
better differentiate CFS from other disorders which share some
CFS symptoms but are not true CFS cases."

Importantly, many people with ME/CFS across the world point
out a key fact, namely that though they are "diagnosed" and
placed under the ME/CFS umbrella:

a) Fatigue is not their primary problem: musculoskeletal pain
and post- exertional myalgia along with other physical signs are
far more prominent, corresponding more closely to the classical
definition of ME. b) The World Health Organisation International
Classification of Diseases (ICD) has, since 1969, classified ME
separately as a neurological problem (ICD 10 93.3), with 'CFS'
incorporated into the current ICD as a sometime synonym for
ME. The chronic fatigue states per se are listed under mental
and behavioural disorders (F 48.0), a category which specifically
excludes ME/PVFS/CFS.

It is now recognised by clinical champions – and by most
charities representing patients in the UK and overseas – that
there is a strong, perhaps overwhelming, case for unpacking the
term 'ME/CFS' and reclassifying and renaming in accordance
with more specific clinical criteria (e.g., De Becker et al 2001;
Tan et al 2002). Indeed, the further categorisation or
substratification on the research-based subsets, or the need for
it, is so often alluded to in the scientific literature on ME/CFS
(vide http://www.cfids-cab.org/MESA/subsets.html) that it is now
a commonplace (though this body of literature has eluded the

Examples in the past two years alone include: Jason,
Neuropsychology Review 2005; Natelson, Clinical and
Diagnostic Immunology 2005; de Lange FP, Neuroimage 2005;
Baraniuk, BMC Neurology 2005; Kaushik N, J Clin Pathol 2005;
Nijs J, Med Sci Sports Exerc 2005; Chia J, Journal of Clinical
Pathology 2005; Lange G, Neuroimage 2005; Reeves, BMC
Med 2005).

Alongside this groundswell for change, there have been
attempts to revise the CDC-1994 criteria directly (e.g., Reeves
2005), including suggestions for subclassification by mode of
onset – rapid post-viral onset versus gradual onset – given that
there appears to be a genetic basis for this distinction. In
addition, the recent Canadian Consensus Document produced
by the Expert Medical Consensus Panel in Canada (Carruthers
2003) was a valiant first attempt at arriving at an
evidence-based yet historically consistent system of
subgrouping patients based on their specific symptoms and
signs. As these authors say, "The CDC [1994] definition, by
singling out severe, prolonged fatigue as the sole major
(compulsory) criterion, de-emphasized the importance of other
cardinal symptoms, including post-exertional malaise, pain,
sleep disturbances, and cognitive dysfunction. This makes it
more difficult for the clinician to distinguish the pathological
fatigue of ME/CFS from ordinary fatigue or other fatiguing
illnesses". The lack of any substantive allusion to this Canadian
Consensus Document (2003) in the current GDG guidelines is a
serious omission, and one which diminishes the authority of the

Our key point is that CFS/ME or ME/CFS is a wide umbrella
term recognised by clinical champions, patient charities, leaders
of ME/CFS support groups, and scientific researchers to
contains many different patient groups. Without addressing this
core issue, the efforts of the GDG to give diagnostic and
management guidance that goes beyond the recommendation
of anodyne, non- specific interventions will be inadequate and
probably constitute misguidance.


2. The skewing of the RCT evidence-base examined by the
GDG, and the devaluation of evidence from scientific studies
and surveys.

While RCTs are the best evidence of "efficacy", there is a
particular problem in the case of the diagnostic rubric ME/CFS.
The large majority of "good quality" RCTs have examined the
use of the non-specific management and coping strategies
cognitive behavioural therapy (CBT) and graded exercise
therapy (GET). Such trials are very expensive to conduct, and
their authors have had the impetus - and been able to access
the resources - to conduct them. This means that systematic
reviews, such as that conducted by the GDG and ancillary staff –
building on Whiting 2001, Mulrow 2001 and Chambers 2006 –
find that the most prominent RCT evidence is for these
non-specific management and coping strategies which (by their
very non-specificity, with inadequate blinding and in the absence
of a truly indistinguishable control intervention) are prone to
result in mildly positive outcomes. The fact that these trials of
CBT and GET have had relatively unspectacular results is less
important to reviewers than the fact that they are "positive".

In short, the accepted strategy of looking at formal "evidence" is
flawed in ME/CFS because the evidence-base is skewed
towards the small group of mildly positive RCTs. It is not a case
of finding the "best" evidence garnered from the work of a range
of biomedical and biopsychosocial scientists working on a level
playing field, but rather finding quite modest evidence in a
forgotten field put there by proponents of one model of the illness
– the biopsychosocial model – a construct which contrasts with
the biomedical model which implies that a primary disease
entity exists and that biopsychosocial aspects are secondary
(the two models discussed in the report to the UK Chief Medical
Officer in 2002). Contrast this situation with, say, breast cancer
which has been well supplied with funding for biomedical trials,
and in which meta- analysis can arrive at a best estimate of
treatment effects from a large number of different studies,
including replicate investigations on different populations by
different research groups (vide NICE Guidance on Cancer
Services Improving Outcomes in Breast Cancer, 2002). Breast
cancer with the formal evidence-base that currently exists for
ME/CFS would be no less a physical illness, and the
non-specific management and coping strategies would be no
more specifically effective for the underlying disease. Our point
is that a NICE guideline on the diagnosis and treatment of
breast cancer in the face of such an evidence-based would not
be meaningful, or fair to the patients.

A corollary of this is that the importance of evidence from
non-RCT scientific studies is diminished or discounted. There is
no need for us to list here the range of biomedical investigations
already conducted on people with ME/CFS – these have already
been flagged for the attention of the GDG, and a full database of
over 3000 abstracts exists at http://www.meresearch.org.uk/.
Most are not RCTs or controlled trials, and come lower in the
hierarchy of research evidence, but given the paucity of clinical
trials in ME/CFS (a function of lack of the basic funding needed
to test hypotheses) and the skewing of the small RCT
evidence-base that exists, they do, in fact, represent a
considerable body of evidence that biomedical investigation can
uncover, within a subgroups of people with ME/CFS, biological
anomalies that might well help to explain many of the clinical
features associated with the illness and indicate areas for
therapeutic treatment.

Similarly, patient survey evidence is largely discounted because,
in the GDG's words (FULL guideline, page 43/269, line 22),
"surveys from self selected respondents are subject to bias and
not necessarily representative of the wider population of people
with CFS/ME". Of course, surveys come low in the hierarchy of
research designs, since they are not deemed valuable for
determining causation or the true effect of treatment, and tend to
come from apparently self-selecting" group of people with
self-reported symptoms. However, there are two things to be
said. First, the evidence for the effectiveness of non- specific
management and coping strategies is itself gathered by
self-selecting professionals promoting their areas of expertise
with access to central funding, and who also have difficulty
ascribing causation or determining the true treatment effects.
Second, such soft survey data contains real, hard experience –
the experience of thousands of patients who have no access to
funding for trials, and no way to publish their experience in the
scientific literature. And while they are limited as formal
evidence yet they are surely not meaningless or valueless. When
they say –as in one large survey (CMO report 2002, page 49) –
that only 7% of respondents found CBT "helpful", compared with
26% who believed it made them "worse", the remaining 67%
reporting "no change", they are not joking, and nor are the 79%
of patients in the same survey who answered that they had
severe pain sometimes, much of the time, or all of the time.
Clearly, community-based surveys can be very useful for
describing the experiences of people with severe and less
severe ME/CFS and can help uncover widespread areas of
concern (such as the lack of community care provision), or
highlight areas where new research is needed (such as the
urgent need for pain relief). In short, they can provide a
systematic record of individual suffering, and point to ways to
alleviate it. In this regard, they should be taken seriously by the

ME Research UK and the wider ME/CFS community are not
alone in pointing out such concerns. The central point was well
put in recent letter (The Guardian, Oct 26 2006) by Dr Stilgoe of
Demos, and Prof Irwin and Dr Jones; "The experiences of
patients and the professional judgments of doctors are
important. It is not a simple battle between evidence and
anecdote....NICE needs to do more than just look at published
science. It needs to start listening to people, patients and


3. The limitations of the evidence base for non-specific
management and coping strategies.

As the recent review by Chambers et al (2006) – which informs
and is informed by the deliberations of the GDG – shows, there
have been only 5 trials of CBT which have a validity score >10,
one of which is negative for the intervention; and only 3 RCTs of
GET with a validity score >10. The total number of available
trials is small; numbers are relatively low; no trial contains a
"control" intervention adequate to determine specific "efficacy";
and their results are relatively modest (for example, one of the
flagship trials [Prins 2001] described as having "cure of chronic
fatigue syndrome as its explicit goal of therapy", reported no
improvement on the fatigue severity endpoint in 56/83 patients
after 8 months and in 38/58 after 14 months. The result was
significantly better than in the control groups, but was modest
nevertheless). In addition, some of the studies (particularly those
on GET) have used the Oxford criteria (Sharpe 1991) for
diagnosis, a rubric which allows selection of patients with
chronic fatigue states, raising the question of the applicability of
their results to patients with specific symptoms and signs. Again,
the heterogeneity of the trials, the potential effect of publication
or funding bias for which there is some evidence, and
professional doubts about the evidence base for some
behavioural therapies themselves give grounds for caution as
regards the usefulness of this evidence-base to direct the
management of people with ME/CFS. A commentary in the
British Medical Journal (Bolsover 2002) is particularly relevant to
the deliberations of the GDG: Until the limitations of the evidence
base for cognitive behavioural therapy are recognised, there is a
risk that psychological treatments in the NHS will be guided by
research that is not relevant to actual clinical practice and is less
robust than is claimed."

These concerns have been echoed by reviews in the past, which
have recommend caution in interpretation of the evidence-base:
Whiting et al. 2001 stated, "all conclusions about effectiveness
should be considered together with the methodological
inadequacies of the studies. Interventions that have shown
promising results include CBT and GET"; and Mulrow et al. 2001
stated, "….it is unlikely that the beneficial effects of such general
treatments are specific or limited only to patients with CFS. In
other words, although these therapies may help some people
with CFS, their effectiveness does not help establish an
underlying aetiology or cause of CFS". Indeed, a large body of
both professional and lay opinion considers that these
essentially adjunctive techniques have little more to offer than
good medical care alone, and questions what specific additional
therapeutic value they bring. As Carruthers et al (2003) have
pointed point out: "The question arises whether a formal CBT or
GET program adds anything to what is available in the ordinary
medical setting. A well informed physician empowers the patient
by respecting their experiences, counsels the patients in coping
strategies, and helps them achieve optimal exercise and activity
levels within their limits in a common sense, non- ideological
manner, which is not tied to deadlines or other hidden agenda."

It would be referable for NICE and the GDG to recognise that
specific, rigorous, evidence-based recommendations for
treatment cannot be made at present than to incorporate an
inadequate evidence-base into established guidelines which
feed into clinical care and government policy to the detriment of
people with ME/CFS.


omitted for clarity)


"...like other chronic illnesses with no certain disease

This leaves open the possibility that there might not be a
disease process at all, when there are thousands of people with
a physical illness.

REPLACE WITH "like other chronic illnesses whose causes
have yet to be discovered and disease processes elucidated...


"... Communication should be supported by the provision of
evidence-based information....."

Given the particular problems with the meaning and relevance of
the RCT evidence in ME/CFS, evidence-based information
should have a wider scope.

REPLACE WITH "Communication should be supported by the
provision of evidence- based biomedical and scientific
information from the international literature, as well as
evidence-based suggestions for coping with symptoms...


"... CBT is an evidence based treatment for CFS/ME...."

It is not. The evidence base consists of only 5 trials which have a
validity score >10, one of which is negative for the intervention
(vide Chambers 2006). Again, "treatment" is too strong a word
for the relatively modest (and probably non-specific) effects seen
in these trials. As proponents of the biopsychosocial model of
ME/CFS (CMO report 2002, page 24) themselves make clear: it
is "not a cure" (Deale 2001); it is "modestly effective" and not
remotely curative" and "not the answer to CFS" (Wessely 2001);
and "...it should be kept in mind that evidence from randomized
trials bears no guarantee for treatment success in routine
practice. In fact, many CFS patients, in specialized treatment
centres and the wider world, do not benefit from these
interventions. When it comes to the management and treatment
of CFS patients, there is still a lot to be learned." (Huibers and
Wessely 2006). We note that the most recently published RCT
on CBT (O'Dowd 2006) states, "...there was, however, no
evidence that the treatment restored normal levels of function for
the majority of patients."

Furthermore, the methodological problems with these trials have
been well- described by Carruthers et al (2003): "The complexity
of CBT studies, their varied inclusion and exclusion criteria, the
very limited portions that can be properly blinded, and the
subjective means used for most evaluations, puts in question the
validity of their results. In addition, the numerous variables
between the CBT studies, the CBTs and control programs, the
different comparison therapies, and the varied frequency and
duration of therapy, make it very challenging to determine which
parts are responsible for any perceived improvement. Are any
effects due to the shift in cognitive beliefs, the exercise involved,
the amount and quality of the attention and counseling, the
discontinuance of other medical therapies during the test period,
etc? Thus the Powell et al [2001] study found GET alone to be as
effective as CBT, and the Ridsdale et al [2001] study found CBT
to be no more effective than counseling."

REPLACE WITH: .... While cognitive behavioural therapy most
likely has some role in helping patients with all illnesses,
including cancer and MS, to better cope with their symptoms
until a cure is found, this role is limited and essentially


"... CBT or psychological approaches to CFS/ME do not imply
that symptoms are psychological, 'made up' or in the patient's
head. It is used in many health settings including cardiac,
cancer, diabetes and chronic pain as well as with mood
disorders such as anxiety and depression...."

This is a disingenuous paragraph. The British Association for
Behavioural and Cognitive Psychotherapies website
(http://www.babcp.org.uk/) states that "CBT is an approach to
help people experiencing a wide range of mental health
difficulties. The basis of CBT is that what people think affects
how they feel emotionally and also alters what they do....CBT
practitioners... aim to work jointly with the person to help them
begin to identify and then change their extreme thinking and
unhelpful behaviour...." CBT is universally recognised to be a
form of psychotherapy used to treat a variety of psychological
impairments, but also used as a therapeutic adjunct for symptom
management and coping in illnesses such as cardiac, cancer,
diabetes and chronic pain. Indeed, we note that when references
to CBT appear in the document, "Multiple Sclerosis: National
Clinical Guideline for Diagnosis and Management in Primary
and Secondary Care" (2004), it is in the context that that
psychological management strategies be employed IF the
patient is depressed or anxious, but not otherwise.

Interestingly, the rationale for using CBT in ME/CFS is that
inaccurate beliefs/ineffective coping maintain and perpetuate
the illness, but it has never been proven that these illness beliefs
have caused or maintain the illness, and correlations (where they
exist) might just as well have arisen from the valid belief that
illness DOES have a physical cause, and that activity avoidance
IS the correct course of action.

The GDG guidelines could follow the NICE Guidelines for
Multiple Sclerosis, and reinforce the adjunctive, supportive role
of CBT in ME/CFS by stating the below:

REPLACE WITH: .... CBT or psychological approaches to
CFS/ME do not imply that symptoms are psychological, 'made
up' or in the patient's head. Rather, they can be thought of as
essentially adjunctive management and coping strategies which
might be useful for some people some of the time.....


"... GET is an evidence-based self-management approach to

It is not. The evidence base consists of only 3 RCTs with a
validity score >10, one of which concludes, "...graded exercise
produces small but clinically significant improvements in case
level fatigue and functional work capacity in CFS patients...."
(Wearden 1998). Given that all three trials recruited patients on
the basis of the Oxford criteria which selects an over-broad
groups of patients including those with idiopathic chronic fatigue;
that there is a strong likelihood of significant non-specific effects
given the design of the studies; and the likelihood that
self-pacing or good quality clinical care would produce similar
small effects much more cheaply (free, in fact), this management
approach cannot be called properly evidence-based or
cost-effective in ME/CFS at present.



"...Severity...These definitions were agreed by the GDG and
have been derived from definitions in the Royal College of
Paediatrics and Child Health Guidelines and the CMO report...."

These three severity levels are not evidence-based. Levels
should be based on clinical observation of clusters of symptoms,
each scored according to severity, to allow accurate ascription
of a patient to a category of severity. The simple but effective
"Symptom Severity Chart" of the Canadian Consensus
Document (Carruthers 2003) – which allows for scoring – would
be a good starting point.

REPLACE WITH: .... Severity...These definitions are ad hoc and
essentially based on mobility, and efforts are underway to derive
a symptom-based scale.


"...they have usually stopped work...."

REPLACE WITH: ...they have usually been forced by illness to
stop working...


"... When the adult or child's main goal is to return to normal

There is a suspicion that this would not be written of patients with
other illnesses, and that it is included to suggest that some
people with ME/CFS could be malingerers.



"... then the therapies of first choice should be CBT or GET
because there is good evidence of benefit for this condition in
mild to moderately affected adults and some evidence in mild to
moderately affected children."

This is not true for adults (as discussed above). As regards
children, the updated systematic review which informs the GDG
(Chambers 2006) says: "The recommendations for children and
young people were largely developed by consensus because of
a lack of specific evidence for this age group. GET and CBT
were recommended for consideration based on extrapolation
from studies in adults. The effectiveness of CBT for adolescents
is supported by a recent high- quality RCT [Stulemeijer 2005]
although this had only 69 participants" (It is also the only positive
RCT on children with a validity score >10.) And the GDG s draft
guidelines subsequently say, in section 4.1, "There is no
evidence for the use or effectiveness of these strategies in these
two patient groups [young people and the severely affected]".



"... When an acute infection is followed by excessive fatigue, the
adult or child should receive advice on how to promote

REPLACE WITH: ... When an acute infection has characteristic
sequelae of ME/CFS, then the adult or child should receive
advice on how to receive treatment and promote recovery.......


"... Healthcare professionals should be proactive in advising
about fitness for work and education..."

This is not a standard phrase used in NICE Guidelines for other
chronic conditions. The GDG should show why it is necessary to
use this phrase here since there is a suspicion that this phrase
would not be written of patients with other illnesses. What
evidence is there – to inform evidence-based guidelines – that
people with ME/CFS need unusual prompting from healthcare
professionals to return to their pre-illness lives and jobs?



"... A documented, individualised management plan should be
developed with the adult or child with CFS/ME, and the carer,
where appropriate to include...... education or employment

As above, this seems to imply that people with ME/CFS need a
healthcare professional to prompt them into education or



"... CFS/ME is recognised on clinical grounds alone...."

The reasons for this, and its implications for the validity of any
guidelines produced by NICE, have been discussed in the long
preamble to these specific comments. However, the
clinical-basedness of the rubric ME/CFS does not mean that
widening it further (as proposed by the GDG – see below) is
sensible. Nor does it mean that other supportive evidence of
illness need be absent. For example:

a) The paper by Devanur and Kerr (2006) expresses the
biomedical evidence well – and there is a range of reviews in a
similar vein: "Studies of pathogenesis have revealed immune
system abnormalities and chronic immune activation,
dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis,
brain abnormalities, evidence of emotional stress (comprising
host aspects) and evidence of exogenous insults, for example,
various microbial infections (Epstein-Barr virus, enteroviruses,
parvovirus B19, Coxiella burnetii and Chlamydia pneumoniae),
vaccinations and exposure to organophosphate chemicals and
other toxins (comprising environmental aspects)."

b) The Canadian Consensus Document (Carruthers 2003) is a
diagnostic guideline distilled from the panel's collective
extensive clinical experience of diagnosing and/or treating more
than twenty thousand ME/CFS patients. The clinical definition
derived "encompasses the broad cluster of symptoms and signs
that give ME/CFS its distinctive character. Diagnosis is based
on these characteristic symptom patterns, which reflect specific
areas of pathogenesis". This is a superb 108-page document
which should inform the deliberations of the GDG.

c) There is clinical evidence, and some research evidence, that
frank signs can be found if clinicians look for them. For example,
of the quadriceps muscle, To our surprise, the patients with CFS
were physically weaker than both the depressed patients and
sedentary subjects" (Fulcher & White 2002), and more generally,
"In all three groups, a majority of patients exhibited muscle
weakness in the lower limbs, and significant numbers of patients
had absent or abnormal reflexes." (Kennedy et al 2004).

NICE has a great opportunity to look beyond the significantly
rudimentary and skewed RCT evidence-base towards a fresh
assessment of the biomedical evidence in ME/CFS, and the
revision of the symptoms and signs in people with the illness. A
full examination of the Canadian Consensus Document (2003)
would be a good starting point.


"...CFS/ME should be considered if an adult or child has fatigue
that is all of the following:..."

This section introduces a novel – and entirely unvalidated –
method of diagnosing" CFS clinically. The criticism of the most
widely used "research" definition – the CDC (Fukuda) 1994 – is
that it is impossibly broad, being based on "fatigue" plus 4/8
concurrent "minor criteria" symptoms, thereby lacking specificity
since it does not, in practice, completely exclude patients with
other biomedical conditions or, indeed, those with a primary
psychiatric basis for their fatigue.

This attempt by the GDG in section to define a clinical
definition – on a basis other than systematised clinical
experience – makes the situation far worse. It introduces a
diagnosis based on "fatigue" plus ONE or more of 9 vague,
ill-defined symptoms shared with many other illnesses. To be
clear, if (as many believe on the basis of evidence) the current
CDC-1994 research definition is an "umbrella term" covering
diverse groups of patients, then NICE is proposing to replace it
with a marquis similar to a circus tent. The widened diagnosis
would include many thousands of patients currently diagnosed
with idiopathic fatigue (most of whom could report at least one of
nine common concurrent symptoms); it would lead to
significantly increased heterogeneity within the diagnostic
category (which could contain a still-working person with a sore
throat alongside a bed-bound person with all 9 symptoms to a
severe degree; yes, they might have the same illness at a
different stage of development, but NICE has no evidence of
that); and it would not be taken seriously since it flies in the face
of other expert opinion. For example, even the CFS Working
Group at the CDC has recommended that symptom severity be
taken into consideration, and standardised outcome measures
be used to improve its specificity (Reeves 2005). Furthermore,
the experts devising the Canadian Consensus Document
(Carruthers 2003) derived a diagnostic rubric based on
characteristic symptom patterns, which reflect specific areas of

The central issue has been put very nicely by Dr Charles
Shepherd of the ME Association in a letter to the BMJ
(December 2004; 329: 1405): "The medical profession has only
itself to blame for the awful mess that currently surrounds
ME/CFS. It has created an illness that covers a wide variety of
fatigue state clinical presentations, with or without psychiatric
co-morbidity, and almost certainly an equally diverse range of
possible pathological and physiological explanations. Doctors
who deal with patients suffering from unexplained abdominal
pain, arthralgia or headaches do not work on the basis that they
all have the same pathoaetiology and will therefore respond to
the same form of treatment. So why apply this form of flawed
logic to ME/CFS?"

The "clinical" revision proposed by the GDG in these guidelines
can only worsen the pre-existing mess.



...physical or mental exertion making symptoms worse..."

This "symptom" is almost synonymous with "characterised by
post-exertion malaise and/or fatigue" of the major fatigue
criteria. Is this an indication that the novel revision of the clinical
criteria by the GDG needs revising?



"...Some serious underlying diseases might present with similar
symptoms and signs as CFS/ME. The following should be
regarded as 'red flags', indicating a higher index of suspicion of
serious underlying pathology.`

Abnormal neurological signs. Features of cardiovascular
problems. Weight loss. Features of sleep apnoea. Features of
anxiety and depression...."

Most patients currently diagnosed with ME/CFS – including the
20,000 members of ME/CFS self-help groups – have arrived
there after some minor clinical investigations by their GPs that
have had negative results. They remain ill, however, and – in the
absence of investigations for clinical signs, or in the face of
disbelief – lose faith in clinical services. However, the umbrella
diagnosis certainly contains seriously people who could benefit
from full and comprehensive clinical examinations, and in whom
alternative diagnoses (e.g. Lyme disease; frank sleep apnoea;
Addison's disease – just some of the re- diagnoses that have
come to our attention) could be found if healthcare professionals
and researchers were motivated to find them.


"...the following tests should not be done routinely....The head-up
tilt test...

...Serology testing for chronic bacterial infections (for example,
borelliosis) in the absence of any indicative history.

.. Serology for chronic virus infections: HIV, hepatitis B and C, in
the absence of any indicative history. ..

..Serology for general viruses (for example, heterophile antibody
tests for infectious mononucleosis) in the absence of any
indicative history.

...Serology testing for latent infections: toxoplasma, EBV
(Epstein Barr virus), CMV (cytomegalovirus) in the absence of
any indicative history."

These recommendations are in direct contrast to those forming
the basis of the Canadian Consensus Document (Carruthers
2003) which have been distilled from the panel's collective
extensive clinical experience diagnosing and/or treating more
than twenty thousand ME/CFS patients. Examples of their
recommendations include the below:

"Autonomic Manifestations

...Orthostatic intolerance is commonly seen in ME/CFS patients
and Includes neurally mediated hypotension (NMH); postural
orthostatic tachycardia syndrome (POTS); and delayed postural

Laboratory and Investigative Protocol

...a) Further Laboratory Testing: diurnal cortisol levels, 24 hour
urine free cortisol; hormones including free testosterone, B 12
and folate levels, DHEA sulphate, 5-HIAA screen, abdominal
ultrasound, stool for ova and parasites, NK cell activity, flow
cytometry for lymphocyte activity, Western blot test for Lyme
disease, hepatitis B and C, chest x-ray, TB skin test and HIV
testing. Do the 37-kDa 2-5A RNase L immunoassay when it
becomes available.

b) Differential Brain Function and Static Testing: MRI: those with
significant neurological finding should be considered for a MRI
to rule out multiple sclerosis (MS), and cervical stenosis.
Quantitative EEG, SPECT and PET Scans and Spectography:
qEEG analysis of brain waves, SPECT estimation of dynamic
brain blood flow and PET analysis of brain metabolism show
diagnostic promise and will become more important as these
techniques are refined and research confirms their diagnostic

c) Tilt Table Test d). Sleep Study; e) 24-Hour Holter Monitoring:
if a significant arrhythmia is suspected. f) Neuropsychological
Testing: can be utilized to identify cognitive dysfunction and/or
confirm diagnosis. If done, it should focus on the abnormalities
known to differentiate ME/CFS from other causes of organic
brain dysfunctions etc......."

There is a clear mismatch between the truncated
recommendations of the GDG, and the routine examinations
recommended by ME/CFS clinicians across the world.



"... When a diagnosis is made, a prognosis of cautious
optimism should be conveyed. With appropriate management,
most children and adults, but not all, will have some improvement
and some will recover fully...."

This is not true (and again the problem involves  "what"
diagnosis and using "which" definition). Two separate recent
reviews have concluded that, "… patients exhibit severe,
long-term functional impairment. Substantial improvement is
uncommon and is less than 6%" (Andersen 2004); and, "Full
recovery... is rare" (Cairns and Hotopf 2005).

REPLACE WITH: .... When a precise diagnosis is made, a
prognosis of cautious optimism should be conveyed. With
appropriate management, most children and some adults can
improve or even recover fully, though the patient must be left in
no doubt that long-tern morbidity can be high....


"....When the adult or child's main goal is to return to normal

There is a suspicion that this phrase would not be written of
patients with other illnesses, and that it is included to suggest
that some people with ME/CFS could be malingerers.



General Global Comments on Guidelines section 1.3
This section consists of recommendations for management that
include: Cognitive behavioural therapy Graded exercise therapy

Neither cognitive behavioural therapy (a form of psychotherapy
designed to manage dysfunctional illness beliefs) nor graded
exercise therapy (which is used as part of a biopsychosocial
programme predicated on a model of physical deconditioning)
are evidence-based to a level that would allow NICE to
recommend that these management strategies be rolled out to
the 120,000–240,000 people with ME/CFS in the UK. In
addition, in the few good quality RCTs which exist, the effect is
modest and non-curative, and there is more than a strong
suspicion that much of the apparent treatment outcome relates
to the non- specific effects, i.e., that good quality usual clinical
care (in the case of CBT) and self-pacing (in the case of GET)
would produce similar results.

Also, the evidence from formal RCTs is opposed by evidence
from patient surveys which overwhelmingly find against the
usefulness of these strategies. As the FULL guideline (56/269,
line 2) states "Graded exercise was felt to be the treatment that
made more people worse than any other. 39% were made
worse by this whereas, in contrast, only 2% were made worse by
diet. Graded exercise was also considered to be the least
helpful treatment or management schedule; only 13% said that it
helped a lot and 26% said that it helped a little [n=347]". Again,
as regards cognitive behavioural therapy, the FULL guideline
(pages, 56 and 58, Table ) states that only "7% reported to be
helped by CBT whereas 67% were unaffected and 26% made

Accordingly, the emphasis on these strategies in the NICE
guideline draft is misplaced, as described in the preamble


...Cognitive behavioural therapy (CBT) and graded exercise
therapy (GET) are comparatively expensive symptom
management strategies which some patients might want to try
until the cause(s) of ME/CFS are unravelled and a cure


"…Cognitive behaviour therapy (CBT) …A programme of CBT
should include: … explanation of the CBT model for CFS/ME…"

There is no CBT model for ME/CFS per se. Rather there is
CBT, a form of psychotherapy, which can be applied to all
illnesses though the supposed biopsychosocial model. Even
though CBT has its critics – such as Holmes (2002), "...the
foundations on which [CBT] rests are not as secure as some of
its proponents would have us believe." – there is some evidence
that it can be used as a tool to help some patients cope with
some symptoms. Its application for people with ME/CFS would
therefore be as a management tool, and not as an overarching
model for the pathophysiology of illness.

REPLACE WITH: ……Cognitive behaviour therapy (CBT) …A
programme of CBT should include: … explanation of how CBT,
a form of psychotherapy, might be a useful as part of a
management strategy for coping with symptoms.


"…discussion of the patient's attitudes and expectations…
…developing awareness of thoughts or expectations, or beliefs
and defining fatigue-related cognitions and behaviour…
…challenging cognitions which may adversely affect
rehabilitation and/or symptom management, for example, fear of
activity and perfectionist beliefs… …decreasing somatic
attributions and addressing symptom overvigilance... …problem
solving using activity management and homework tasks to test
out alternative thoughts or beliefs…"

Such sentences, characteristic of proponents of the pure
generalist biopsychosocial model, have been given undue
prominence by the GDG. There is a suspicion that they would
not be so prominently displayed in NICE guidelines for other
illnesses; indeed, we note that they do not appear in the
document, Multiple Sclerosis: National Clinical Guideline for
Diagnosis and Management in Primary and Secondary Care
2004" (despite the fact that fatigue is one of the dominant
symptoms of most people with MS) which recommends (on the
basis of three positive trials of CBT for MS) that psychological
management strategies be employed IF the patient is
depressed or anxious, but not otherwise.

A quote from the Canadian Consensus Document (Carruthers
2003) expresses well how many ME/CFS patients and charities
feel when they see such statement so prominently displayed:
"…there is much that is objectionable in the very value-
laden…hypothesis, with its implied primary causal role of
cognitive, behavioural and emotional processes in the genesis
of ME/CFS. This hypothesis is far from being confirmed, either
on the basis of research findings or from its empirical results.
Nevertheless, the assumption of its truth by some has been used
to influence attitudes and decisions within the medical
community and the general cultural and social milieu of ME/CFS.
To ignore the demonstrated biological pathology of this illness,
to disregard the patient's autonomy and experience and tell
them to ignore their symptoms, all too often leads to blaming
patients for their illness and withholding medical support and
treatment…Crucially, there is a serious question mark over
whether a program of formal CBT or GET program adds
anything to what is available in the ordinary medical setting".



"...Health professionals should be aware that there is no
evidence for the following strategies: ....those which encourage
complete rest (cognitive, physical and emotional) during
significant increases in symptoms..."

There is well-founded support from patient surveys and from
established ME/CFS clinicians that during periods of
stabilisation of illness (as well as in the very early post-infectious
phases) periods of rest are very important (vide Shepherd and
Chaudhuri 2001).


"..Adults with mild or moderate CFS/ME should be offered a
programme that includes planned increases in duration of
physical activity/exercise followed by increases in intensity
leading to aerobic exercise (that is, exercise which increases
the pulse rate) such as GET...."

Much of the current thinking about ME/CFS is driven by models
of deconditioning, predicated on the belief that deconditioning is
a factor in the perpetuation of the illness. However, there is good
evidence that deconditioning is not a significant factor
(Brazelmans 2001; Van der Werf 2000) and that it cannot
account for delayed post-exertional symptoms or the
documented changes in muscle metabolism (Lane 1998 and
2000). Historically, Myalgic Encephalomyelitis is characterised
by a delay in muscle recovery after exercise (with pain and
fatigue 24 or 48 hours after exertion), a phenomenon which few
have studied and which the deconditioning hypothesis does not

In modern ME/CFS patients, there is both clinical and anecdotal
evidence that exercise can exacerbate symptoms and cause
relapse, particularly the some 50% of the patient group whose
illness had a post-infectious onset. One study, however, has
confirmed patient's experience by demonstrating that CFS
patients fail to recover properly from a fatiguing exercise
protocol and that the failure was more pronounced after 24 hours
(Paul 1999). Further, the new "CFS Toolkit for Health Care
Professionals: Managing Activity" (2006) produced by the CDC
in Atlanta (vide http://www.cdc.gov/cfs/toolkit.htm) is clear that
"Advising patients who have chronic fatigue syndrome to
engage in aerobic exercise... can be detrimental. Most CFS
patients cannot tolerate traditional exercise routines aimed at
optimizing aerobic capacity. Instead of helping patients, such
vigorous exercise can cause postexertional malaise, a hallmark
of CFS that is defined as exacerbation of fatigue and other
symptoms following physical or mental exertion. Even worse, this
kind of exercise can precipitate a full-scale relapse that lasts for
days or weeks. A different way of defining exercise and
managing activity is needed for CFS patients and their health
care team." And a similar view is expressed in the Canadian
Consensus Document (Carruthers 2003) "Exercise
programmes must be entered cautiously as clinical studies have
indicated that symptoms worsened in approximately half of the
ME/CFS patients". And again, Dr Charles Lapp re-emphasised
at the American Association for Chronic Fatigue Syndrome
(AACFS) 6th International Conference in 2003, "....although may
clinicians have heard that graded exercise can be helpful,
patients should not embark on an exercise regime which
increases the severity of illness, a phenomenon occurs, as many
experienced clinicians recognise, when patients push
themselves too much". Finally, people with ME/CFS themselves
consistently report the phenomenon of post-exercise worsening
of symptoms: in one report of 1,214 patients graded exercise
therapy was reported to make 50% of patients worse (CMO
report 2002) - the greatest number of 'worse' reports of any
therapy; and the survey of the severely affected (25% ME Group,
2004) found 82% of ME patients reporting that exercise therapy
worsened their condition, with only 5% finding it useful.

There may be sound physiological reasons for the specific
post-exercise malaise encountered. First, post-viral fatigue
(which is not related to the muscle disuse and deconditioning
that can result from the initial period of illness; Lane 2003) might
result in a long-term smouldering infection involving glutathione
depletion (Pierce and Pierce 2006), and be exacerbated by
exercise; or there might be an exercise-induced
physiologically-significant delivery of free radicals, not because
of disuse of muscle and deconditioning, but because there is
something organically wrong with muscle metabolism and/or
vascular endothelial function. Whatever the reason, it is
important to remember that the current evidence for
deconditioning from the psychosocial literature is not based on
scientific investigations of muscle but on suppositions about
patients with "fatigue".

Thus, issues regarding the role of rest and exercise (whether in
the form of GET or not) for people with ME/CFS is not as
clear-cut as the GDG suggests. And, as Shepherd (2001) has
pointed out, physicians must take as much care in prescribing
appropriate exercise as in prescribing medications to ME/CFS
patients. And physicians should only approve of exercise
programs in which the patient's autonomy is respected,
appropriate pacing is encouraged, fluctuations in severity of
symptoms are taken into account, and adequate rest periods
are incorporated (Carruthers 2003).



"...Management of Setbacks.. People with CFS/ME have
variations in the severity of their symptoms and will experience
setbacks or transient increases in fatigue and other symptoms.."

The usual term used in the ME/CFS literature is "crash" (e.g.,
Carruthers 2003) or "relapse" (e.g., CDC, "CFS Toolkit for
Health Care Professionals: Managing Activity" 2006). Relapses
are reported to occur frequently in people with ME/CFS, and can
be long-lasting and affect all areas of life, and be much more
than transient.



"1.4 Key principles of care for people with severe CFS/ME...."

It is generally agreed that severely affected people could make
up 25% of the total number of ME/CFS patients, though some
estimates put the figure higher; the late Dr Melvin Ramsay, the
doyen of ME patients in the UK, stated that one third of patients
experience "a severe and debilitating downhill course", and one
Members Survey of November 2000 reported some 34%
classifying themselves as severely affected. It is surprising then
that the care and management of people with severe illness
takes up only 1.5 pages in the guideline draft produced by the

For the benefit of the Guideline Development Group, the article
by Crowhurst (2005) is an excellent starting point for the
development of meaningful and patient-specific principles of
care; indeed the tabled section, "impact and service response"
would do credit to NICE guidelines, and we hope NICE will
consider their incorporation in its final document. `


"....GET may be an appropriate addition to help patients to
develop their physical capacity and functioning.... "...Activity
management should be the core therapeutic strategy but
elements of CBT may be suitable for some adults and

This is disingenuous. As regards activity, a survey by The 25%
Severe ME Group (2004), 82 per cent of patients with severe
ME/CFS stated that their condition was exacerbated by graded
exercise therapy, of which activity management is a satellite in
this context (as stated in section on the NICE Guideline
draft). Also, the statement that follows this section (NICE
Guideline draft Section 4.1) states: "There is no evidence for the
use or effectiveness of these strategies in these two patient
groups [children and the severely affected].... Patient experience
suggests that some of these interventions may be harmful and/or
not effective....."

The support for the statement of the possible usefulness of CBT
for the most severely ill patients is a single report in the scientific
literature (Powell et al, 1999) which describes two
wheelchair-bound patients who had dramatic improvements in
health following a the "pragmatic rehabilitation regimen". Two
other seemingly relevant reports in the scientific literature are, in
fact, small pilot studies that refer to inpatient treatments within
psychiatric wards (vide Chalder et al 1996 and Essame et al
1998). `


General Comment on section 1.3.4 "Pharmacological

There is now much clinical experience to inform this section –
which comprises only 1.5 pages in the NICE guideline. For
example, recent reviews (Carruthers 2003; Shepherd and
Chaudhuri 2001; and Spotilla 2005) have much to say, and
revisions to this guideline should reflect these.


General Comment on section "Research recommendations" -
page 258 Full Guidelines

The research recommendations consist of refining existing
biopsychosocial coping strategies, assessing their
cost-effectiveness, looking at rates of prevalence, and tinkering
with outcome measures. Crucially no research
recommendations are given for strategies to uncover the
cause(s) of the illness or find a cure.

While the GDG were asked to produce a guideline on
"Diagnosis and Management", the very remit begs the
questions: Diagnose what, and manage what? ME/CFS is a
diagnosis of exclusion – albeit one that the NICE guideline draft
would widen impossibly (see above) – containing patients who
apparently do not fit squarely into any other category. The human
beings inside it are a heterogeneous group who might all have
the same illness at varying degrees of severity, but might not -
the GDG doesn't know where the truth lies, but fills the gap with
general non-specific management and coping strategies which
might help some in a modest way but solve nothing for most.

A programme of research is indeed urgently required, but to
boost and extend physiological and biochemical abnormalities
found in groups of patients meeting the broad criteria for
ME/CFS. Examples of anomalies that can be found include:
Oxidative stress (e.g. Kennedy 2005); Dysregulation of anti-viral
pathways (e. g., De Meirleir 2000); Endothelial dysregulation
(e.g., Khan 2004); Altered brain perfusion (e.g., Tirelli et al.,
1998); Orthostatic hypotension (e.g., Spence and Stewart
2004); Brain metabolic abnormalities (e.g., Chaudhuri et al.,
2003); and Cardiac anomalies (e.g., Lerner 2004); Altered
muscle metabolism (e.g., Fulle et al., 2003); Abnormal response
to exercise ((e.g., McCully et al., 2004); Enteroviral sequences in
muscle (e.g., Lane et al., 2003) ....and so on........



Comparisons between the FULL guideline and the NICE

Since the shorter NICE guideline is the one read by 99% of
interested parties, including healthcare professionals, it is
important that the caveats of the FULL version be reproduced in
the NICE version. These include:

a) …The GDG did not regard CBT or other behavioural
treatments as curative or directed at the underlying disease
process, which remains unknown. Rather, such treatments can
help some patients cope with the condition and consequently
experience a improved quality of life….

b) ...substantial number of patients will pursue a fluctuating
course with periods of relative remission and relapse, and a
significant minority become severely, and perhaps, permanently
disabled.... .... recovery rates of 8% to 63% (median 40%), with
full recovery being rare (5– 10% achieving total remission)...

c) ...the GDG considered that patients should take the lead on
any behavioural approaches to manage their CFS/ME. The
objectives of any programme must be agreed with the patient
who must understand the aims and objectives and must be
willing to take part.....



1. The Analysis Report (2004) by the 25% ME Group for Severe
Sufferers which was submitted to the Guideline Development
Group previously, is not mentioned in either the FULL or the
NICE guidance. This reported that 93% of respondents found
CBT unhelpful and that GET was found to be unhelpful by 95%. It
may be, as the FULL guideline says (page 43/269, line 22),
"surveys from self selected respondents are subject to bias and
not necessarily  representative of the wider population of people
with CFS/ME". But this report is still valuable and full of meaning,
coming from a group representing over 1000 house- and
bedbound people with ME/CFS, and does not deserve to drop
off the edge of the evidential world.

2. There is a need for clear criteria for referral to
psychology/psychiatry services. The guideline draft is vague
regarding the circumstances under which a patient can be
referred for cognitive behavioural/graded exercise and other
similar interventions, and for psychiatric/psychological
assessment. We understand this to be an area of great concern
for some people with ME/CFS, and so we feel that precise
criteria for such referrals should be published as part of the final
guidelines. Openness is a key element of modern NHS reform,
and the publication of clearly-defined criteria would be both a
major step towards reassuring  parents and carers, and a
signpost for professionals working in this area. The concern of
some people with ME/CFS is that unless this is done, most
cases will be referred for psychology/psychiatry services
routinely. Given some of the statements in the current draft  -
which can read as thinly-veiled invitations to uncover
psychological dysfunction - these concerns may, in fact, be valid.

3. The GDG fails to make a positive statement about the
entitlement of people with ME/CFS to Disability Living
Allowance/Incapacity Benefit. This is a perplexing issue for the
many thousands of people with this illness who rely on disability



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[Return to top]


Date:    Wed, 29 Nov 2006 12:52:45 -0500
From:    "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx>
Subject: RES: Women's Health Issues with Fibromyalgia Syndrome

Women's Health Issues with Fibromyalgia Syndrome.

J Womens Health (Larchmt). 2006 Nov;15(9):1035-45.

Shaver JL, Wilbur J, Robinson FP, Wang E, Buntin MS.

University of Illinois at Chicago, College of Nursing, Chicago, Illinois.

PMID: 17125422

Background: Fibromyalgia syndrome (FMS) involves multiple sensory, somatic,
and cognitive symptoms that are bound to affect or be affected by physical
and mental health status and behavioral components of daily life.

Methods: From a telephone survey of 442 women with and 205 women without
FMS as volunteers, data were compared on (1) general health status, (2)
reproductive and sleep-related diagnoses, and (3) lifestyle health behaviors.

Results: All multiple or logistics regression analyses for group
differences were controlled for age, body mass index (BMI), race,
employment status, marital status, having a college degree, low household
income, and having ever been diagnosed with depression, with a Bonferroni p
value correction for multiple indicators. Accordingly, FMS negatively
impacted both perceived physical and mental health status, although
relatively more so for physical (p < 0.017). Women with FMS were more
likely to have had reproductive health or sleep-related diagnoses,
including premenstrual syndrome, dysmenorrhea, breast cysts, bladder
cystitis, sleep apnea, restless leg syndrome, and abnormal leg movements (p
< 0.0125). They were calculated to use less than half as many calories per
week as control women (689 ± 1293 vs. 1499 ± 1584 kcal/week, p < 0.05)
and had more sleep pattern difficulties (p < 0.0125), more negative changes
in sexual function (greater odds for 5 of 10 indicators at p < 0.005), and
lower alcohol use (odds ratio = 0.39, p < 0.05).

Conclusions: Patients with FMS deserve careful assessment for reproductive
conditions and sleep-related functional disorders. Besides more research
into mechanisms underlying symptoms, intervention testing specifically to
alleviate sleep problems, low physical activity levels, and sexual
dysfunction should be paramount.

[Return to top]


Date:    Wed, 29 Nov 2006 13:38:38 -0500
From:    Co-Cure Moderators <co-cure-mod@xxxxx.xxx.xxx>
Subject: NOT,MED: Dr. David Bell on "Intravenous Fluid as a Treatment for ME/CFS"

Dr. David Bell on "Intravenous Fluid as a Treatment for ME/CFS"
by Dr. David S. Bell, MD, FAAP


Reproduced with permission from the November 1, 2006 issue of the
_Lyndonville News._ Dr. Bell is a widely published, internationally known
expert on adult and pediatric ME/CFS, practicing in Lyndonville, New York.

The newsletter today is my first discussion of intravenous saline as a
treatment agent for ME/CFS. I have now been using this treatment for nearly
six years and wish to share my thoughts. While I plan to be open, honest
and even blunt about this treatment, I will not compromise the
confidentiality of the patients treated. I have nothing to sell, and I am
not encouraging this treatment, as it has not been rigorously tested.
However, I do not think I am witnessing a placebo response, and all things
considered, it is the most effective treatment for severe ME/CFS that I
have found in my 21 years of looking. But it has serious drawbacks and risks.

Read the complete article at

[Return to top]


Date:    Wed, 29 Nov 2006 20:08:08 +0100
From:    Jan van Roijen <j.van.roijen@xxxxx,xx>
Subject: med: Therapeutic method for treating Epstein-Barr virus infection


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 >>>> 27 November 2006     <<<<
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From:  DEnlander@xxx.xxx

Therapeutic method for treating Epstein-Barr virus infection

Type and Number:
United States Patent 5334395

Link to this page:

A therapeutic method for treating Epstein-Barr virus infection.
The method comprises administering a therapeutically-effective
amount of a mammalian liver extract, the extract being
characterized by being heat stable, insoluble in acetone and
soluble in water, peptide or peptide fragment selected from the
groups consisting of Sequence Identification Numbers 1-9.

[Return to top]


Date:    Wed, 29 Nov 2006 21:12:23 +0100
From:    Jan van Roijen <j.van.roijen@xxxxx.xx>
Subject: res: ME/CFS -Ampligen -Phase III study


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Major Late-Round Ampligen® Trial Recruits in Seven States

by Editor ImmuneSupport.com


An open label Phase III "intervention" study of the antiviral drug
Ampligen® 511 - the most recent step in Hemispherx
Biopharma's decade-long quest for FDA approval of the drug as
a CFS therapy - is recruiting subjects with "severely debilitating"
CFS/ME at centers in seven states, nationwide, according to
ClinicalTrials.gov:   http://clinicaltrials.gov/

Locations and Principal Investigators

The "chairs" or principal investigators of the trial, titled "An Open
Label Study of Ampligen® in Chronic Fatigue Syndrome,"
include three of the leading American names in CFS treatment:

      *   Daniel Peterson, MD, Sierra Internal Medicine,
      Incline Village, NV

      *   Lucinda Bateman, MD, Fatigue Consultation
      Clinic, Salt Lake City, UT

      *   Charles W. Lapp, MD, Hunter-Hopkins
      Center, Charlotte, NC

The other four listed trial locations include Los Altos, CA;
Springfield, NJ; Philadelphia, PA; and Reston, VA.

Trial Design and Purpose

Hemispherx noted recently that a previous, not-yet-published
Phase III (large) randomized placebo-controlled Ampligen® trial
enabled the group of CFS patients who received the drug for
twice weekly for 40 weeks to increase their exercise tolerance
by an average of 15 percent compared with another group of
CFS patients who were randomly selected to receive the
placebo (fake dose).

The current trial, officially titled An Open Label Study of
Ampligen® in Chronic Fatigue Syndrome (ClinicalTrials.gov
Identifier: NCT00215813) will be:

      *   An expanded access (large-population)
      interventional trial to study and analyze in more
      detail the drug's safety and effectiveness in
      affecting CFS symptoms among a large group
      of patients with "severely debilitating CFS/ME."

      *   Open label, non-randomized, and
      uncontrolled. All patients will knowingly be
      receiving the drug Ampligen® (Poly I: Poly
      C12U). None will receive placebo.

      *   And importantly, the FDA has "approved the
      study for cost recovery." This means patients
      enrolled in the study will be responsible for
      paying costs relating to the therapy – including
      the cost of the drug itself, and the cost of
      infusions, supplies, and diagnostic and other
      lab testing.

Though the trial-related costs are not specified, the drug is likely
to be quite expensive if and when the FDA's follow-up research
supports approval of Ampligen® as a CFS therapeutic. Some
project that the drug would cost $15,000 to $20,000 per patient
per year, according to a recent article in Science News. (The
co-inventor of Ampligen®, William A. Carter, MD, pioneered the
clinical development of the antiviral therapy interferon, which now
pulls down annual sales of $2 billion-plus.)

Eligibility and Inclusion Criteria:


Diagnosis of Myalgic Encephalomyelitis (ME) as defined by the
1988 Centers for Disease Control and Prevention (CDC) case
definition for Chronic Fatigue Syndrome (CFS); ongoing for at
least 12 months. (Other clinical conditions which could present
with similar symptoms must be excluded.)

Age Range
Ages 18 through 65.

Males or non-pregnant, non-lactating females
Females must be of non-child bearing potential (either
post-menopausal for two years or surgically sterile including
tubal ligation), or using an effective means of contraception (birth
control pills, intrauterine device, diaphragm).

Females who are less than two (2) years post-menopausal,
those with tubal ligations, and those using contraception must
have a negative serum pregnancy test within the four (4) weeks
prior to the first study medication infusion.

Females of child bearing potential agree to use an effective
means of contraception from four (4) weeks prior to the baseline
pregnancy test until four (4) weeks after the last study medication


A reduced quality of life as determined by a Karnofsky
performance score (KPS) of from 20 to 60 at baseline. The KPS
must be rounded in increments of ten (10).

Ability to provide written informed consent indicating awareness
of the investigational nature of this study.

Documentation (during baseline or historically following onset of
CFS/ME) of:

      *   A negative antinuclear antibody test (ANA) or
      a negative anti-ds (double-stranded) DNA,

      *   A negative rheumatoid factor,

      *   And an erythrocyte sedimentation rate

Documentation during baseline of a normal T4 (or other
laboratory evidence that the subject is euthyroid [normal thyroid])
is also required.

Contact Information

Please refer to this study by ClinicalTrials.gov identifier

Sharon Conway 215-988-0080 sharon@hemispherx.net

Please contact Hemispherx Biopharma for additional
information regarding trial locations and site contacts:

By Fax: 215/988-1739

E-mail: trialinfo@hemispherx.net

Mail: Hemispherx Biopharma, Inc. One Penn Center
1617 JFK Blvd., 6th Floor
Philadelphia, PA 19103

More Information

Study ID Numbers: AMP 511 Last Updated: October 24, 2006

Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2006-10-27

[Return to top]


Date:    Thu, 30 Nov 2006 04:18:58 +0100
From:    Jan van Roijen <j.van.roijen@xxxxx.xx>
Subject: med: CDC: Chronic fatigue syndrome is real


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CDC: Chronic fatigue syndrome is real

By KIM ARCHER World Staff Writer


A local medical director says the hardest part of getting help can
be finding a physician who believes you.

After years of ridicule and dismissal, chronic fatigue syndrome
sufferers may feel validated since the U.S. government has
declared the disease real.

In early November, the national Centers for Disease Control
launched an awareness and educational campaign called, "Get
Informed. Get Diagnosed. And Get Help." The campaign is
aimed at educating patients and doctors about the reality of
chronic fatigue syndrome, or CFS.

Eighty percent of an estimated 1 million Americans with the
disease do not know they have it, the CDC said.

"This is a disease that has been shrouded in a lot of mystery and
controversy. And sometimes people question if it's real or not
real," Centers for Disease Control Director Julie Gerberding
said earlier this month. "We are committed to improving the
awareness that this is a real illness and that people need real
medical care and they deserve the best possible help that we
can provide."

"It's very frustrating (to treat CFS patients)," said Robert Gray, a
medical doctor who once treated CFS patients but quit his Tulsa
practice to become medical director of OMNI Medical Group
sponsored by St. John Health System.

He said the CDC's step toward legitimizing the disease is a
good one in that it protects patients from "snake oil salesmen"
and provides doctors with evidence.

He said one of the biggest difficulties in diagnosing and treating
the disease is finding a doctor who believes it is a real illness.

"Most doctors have a strong bias that it's probably a psychiatric
syndrome," he said.

A recent study showed that doctors with loved ones or long-term
patients who suddenly fall ill with CFS are more likely to become
advocates for sufferers. "When they see this was not a needy
person, but an active, accomplished person who became
crippled, they probably can reconcile their preconceptions with
the facts," Gray said.

The CDC also announced $4 million in research grants for

After 20 years of research, the scientific community still does not
know what causes the disease or how to treat it. Scientists have
revealed the discovery of underlying biological abnormalities,
which could suggest a genetic link.

Kim Archer 581-8315

What is CFS?

Chronic fatigue syndrome is a debilitating, complex disorder
characterized by profound fatigue, and often accompanied by
weakness, muscle pain, memory impairment, insomnia and
post-exertional fatigue lasting longer than 24 hours.



Posted on Wed, Nov. 29, 2006

Once dismissed as malingering,
chronic fatigue syndrome finally getting respect

By Nancy McVicar

South Florida Sun-Sentinel


FORT LAUDERDALE, Fla. - Marly Silverman had a high-energy
job as a financial consultant to a major U.S. bank, until she came
down with a viral infection that she couldn't seem to shake. She
was exhausted all the time, ran a low-grade fever and lost
weight, and then the neurological symptoms began.

"I would be driving on I-95 and forget where I was going - not a
good thing," said Silverman, 52.

It took several months, but eventually she was diagnosed with
chronic fatigue syndrome, the Rodney Dangerfield of diagnoses.

For years, people who complained of the symptoms -
exhaustion, joint pain, sleep problems, impaired memory,
inability to concentrate - were dismissed by some doctors as
malingerers or hypochondriacs.

This month, the federal Centers for Disease Control and
Prevention launched a campaign to change that by educating
patients and physicians that chronic fatigue syndrome, or CFS,
is a mysterious but serious disease sometimes triggered by a
viral infection but with other unknown factors.

It affects at least 1 million Americans, but many have not been
diagnosed because most doctors have not been trained to
recognize it, said Dr. William Reeves, chief of the chronic viral
diseases branch at the Centers for Disease Control. Women
are affected at about four times the rate as men, and non-white
women are affected at a rate greater than white women, Reeves
said. The age group most affected is 40 to 59.

Reeves, who leads a research group studying the syndrome,
said the illness follows a pattern of symptoms that can change
over time, and that sometimes disappear and then come back.
Spontaneous recovery is rare, he said.

Treatment plans typically involve doctors asking patients which
symptoms most affect their quality of life - such as
sleeplessness, joint pain, gastrointestinal complaints or
depression - and prescribing medications to ease those

Irwin Auster, who facilitates some of the meetings, said he
sought help from a dozen different doctors for his unexplained
physical pain, but none could figure out what was causing it or
give him anything strong enough to take it away.

"I was on the verge of ending my life, by sitting on the tracks and
waiting for the train," said Auster, 64.

Then he read an article about Dr. Nancy Klimas, a University of
Miami School of Medicine clinician-researcher, who treats
patients with symptoms like his.

"I do owe her my life," Auster said. "I really do."

Klimas, who was in Washington for the launch of the CDC
campaign, said research over the past 20 years is beginning to
figure out the biological underpinnings of the syndrome, which
she thinks is badly misnamed.

"If it were called chronic neuroinflammatory disease, then people
would get it," she said. "Up until now nobody's been willing to
change the name, but now there's proof (that inflammation
occurs in the brain.)

"There's evidence that the patients with this illness experience a
level of disability that's equal to that of patients with late-stage
AIDS, patients undergoing chemotherapy, patients with multiple

Klimas is president of the International Association for Chronic
Fatigue Syndrome, an organization of medical professionals
and research scientists. Its next research conference will be in
January in Fort Lauderdale.

She and other investigators have shown that different types of
cells within the immune system are abnormal either in number or
their capacity to function in these patients.

University of Miami researchers, including Mary Ann Fletcher,
have just been awarded new grants from the National Institutes
of Health to continue their work. One goal is to come up with
tests to diagnose the disease in its different forms, Fletcher

"We have fairly good reason to believe that CFS is not a
homogeneous syndrome. There may be several subsets, and it's
important to compare apples to apples. It's possible a treatment
that would work for subset A would not work for subset B,"
Fletcher said.

Klimas and Fletcher are recruiting 150 new patients for a study
that will assess them on days when they feel good and also
when they're feeling particularly bad, so they can compare their
blood samples for differences.

"And if on a bad day they are unable to come to the clinic, we will
send somebody to them to draw their blood," Fletcher said.

Klimas said even though researchers still don't have all the
answers, there are effective treatment strategies that do help

"There's no single treatment that fixes the illness, but there are
treatments that do help significantly - increasing the function of
the patient, and allowing them to engage in normal activities of
daily living," she said. "It's critical for patients and their health
care providers to know that there is hope and that we can help."



Chronic fatigue syndrome can cause symptoms so severe that
people cannot function normally. There is no simple test to
diagnose the illness, but researchers, including a group at the
University of Miami, are working on that and on how best to treat
the syndrome.

The U.S. Centers for Disease Control and Prevention says
doctors should consider CFS in patients with six months or more
of unexplained fatigue accompanied by other characteristic
symptoms, including:

      *  Cognitive dysfunction, including impaired
      memory or concentration.

      *  Exhaustion lasting more than 24 hours after
      physical or mental exercise.

      *  Unrefreshing sleep, joint pain without
      redness or swelling, or persistent muscle pain.

      *  Headaches of a new type or severity.

      *  Tender lymph nodes or sore throat.


The CDC has more information at www.cdc.gov/cfs. A local
patient group, PANDORA, or Patient Alliance for
Neuroendocrine-immune Disorders Organization for Research
and Advocacy, has a Web site: www.pandoranet.info.

[Return to top]


Date:    Thu, 30 Nov 2006 11:46:17 -0500
From:    "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx>
Subject: RES: Differential efficacy of a cognitive - behavioral  intervention versus pharmacological treatment in the management of  fibromyalgic syndrome

Differential efficacy of a cognitive - behavioral intervention versus
pharmacological treatment in the management of fibromyalgic syndrome.

Psychol Health Med. 2006 Nov;11(4):498-506.

Garcia J, Simon MA, Duran M, Canceller J, Aneiros FJ.

Department of Psychology, University of A Coruna, Spain.

PMID: 17129925

Given that studies about the differential efficacy of existing treatments
in fibromyalgia syndrome are scarce, the aim of this study was to compare
the differential efficacy of a cognitive - behavioral and a pharmacological
therapy on fibromyalgia.

Using a randomized controlled clinical trial, 28 fibromyalgic patients were
assigned to one of following experimental conditions: (a) pharmacological
treatment (i.e., cyclobenzaprine), (b) cognitive - behavioral intervention
(i.e., stress inoculation training), (c) combined pharmacological and
cognitive - behavioral treatment and (d) no treatment.

The results show the superiority of cognitive - behavioral intervention to
reduce the severity of fibromyalgia both at the end of the treatment and at

We conclude that cognitive - behavioral interventions must be considered a
primary treatment of fibromyalgia syndrome.

[Return to top]


Date:    Thu, 30 Nov 2006 11:49:43 -0500
From:    "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx>
Subject: RES: Mechanisms of Disease: genetics of fibromyalgia

Mechanisms of Disease: genetics of fibromyalgia.

Nat Clin Pract Rheumatol. 2006 Dec;2(12):671-8.

Ablin JN, Cohen H, Buskila D.

JN Ablin is a senior physician in the Department of Rheumatology, Tel-Aviv
Sourasky Medical Center and at the Sackler Faculty of Medicine, Tel-Aviv
University, Israel.

PMID: 17133252

Fibromyalgia is characterized by widespread pain and tenderness, and has a
significant familial component. The etiology of fibromyalgia remains
unclear, but genetic factors seem to have a significant role, and are
influenced by environmental factors.

Research over the past two decades has demonstrated that genetic
polymorphisms in the serotoninergic, dopaminergic and catecholaminergic
systems of pain transmission and processing are involved in the etiology of
fibromyalgia, but additional candidates continue to emerge.

Fibromyalgia is thought to belong to the group of affective spectrum
disorders, which include related psychiatric and medical disorders. As the
concept of affective spectrum disorders continues to evolve, progress in
the understanding of the genetic basis of related functional disorders,
such as irritable bowel syndrome and post-traumatic-stress disorder, is
aiding our understanding of the genetic basis of fibromyalgia.

[Return to top]


Date:    Thu, 30 Nov 2006 18:41:44 +0100
From:    Jan van Roijen <j.van.roijen@xxxxx.xx>
Subject: act,med: NICE Submission - Tymes Trust


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From:  "Ian McIlroy" <ian@xxxxx.xxx.xxx>



We are now able to make public our submission to NICE.
Please note that we quote from a new publication - 'The
Nightingale Definition of Myalgic Encephalomyelitis (ME)' - with
which our Executive Director was asked to assist. This is now on
the publications page at www.tymestrust.org and at the
Nightingale Research Foundation's website. Our submission
aims to complement those of many other ME organisations and
add something new to the debate, rather than reiterate all the
points so excellently made already. We particularly concentrate

a) the need to separate out ME from CFS and

b) the need to provide proper advice on children.

All comments are on the NICE version of the Guideline, the
version that would be the most read. Where comments refer to
specific page numbers we have inserted them in this
transcription. Other comments are 'general'.


The Trust believes that the present draft of the NICE guideline on
CFS/ME is unacceptable, and not fit for purpose for patients
suffering from ME.


The problem NICE faces is that it has attempted to put together
guidance on a medical condition that has been artificially
constructed. CFS is not a discrete disease, it is an arbitrary
grouping of symptoms, now with the profile even further widened
by NICE. By the very nature of the process by which 'CFS' was
created, different pathologies must be trapped within its remit;
descriptions of CFS always refer to it as a 'heterogeneous
condition' eg the Report of the Chief Medical Officer's Working
Group on CFS/ME published by the DOH in 2002.

Those who coined the term CFS were divided as to the
symptom profile they would research, rather than researching a
specific and recognisable disease. Government, physicians and
patients are all having to deal with the fall-out of this process.

In the Trust's opinion, this guideline as it stands would lead to an
unprecedented degree of iatrogenic injury to people with
genuine ME, particularly children, those in the early stages of
ME, and the severely ill. Those who are not yet severely ill risk
being made so, both by the treatments recommended, and by
the fact of relapses being trivialised by the term 'setbacks' and
patients being urged to continue with programmes despite these
setbacks. This is demonstrated in the many accounts we have
been given over the years, together with numerous patient
surveys such as that by the 25% Group. If a key symptom of a
disease is post-exertional malaise, it is illogical and
inappropriate to prescribe exercise as a treatment and the
damage done by such an approach is evident in patient

Before CFS was born (originally for research purposes only)
'ME' was the name for a well-defined, virally triggered, potentially
severe and chronic neurological disease. Incorporating it into a
collection of symptoms in which 'chronic fatigue' is the main
symptom masks its true nature. The fact that the CFS construct
has been taken into clinical use compounds the problem. This
has put NICE in the position of issuing guidance on an
unscientific basis, for a hopelessly mixed group of patients.

Consequently, if this guideline were published, physicians face
the stark choice of ignoring NICE when dealing with patients
who have ME rather than CFS, or risking actively causing harm
to this group of patients. They would also have no guidance on
how to distinguish this group.

Having seen and experienced what comes of trying to put
together guidance for 'CFS/ME', the Trust now believes that ME
and CFS should be the subject of separate guidelines. Despite
the step forward that the (recently updated) Canadian Criteria for
CFS/ME represented -criteria which the Trust was the first to
recommend in the UK - we believe that ME should now be
removed from the CFS bracket and steps taken to issue
guidance to doctors as to its true nature, using information from
appropriate ME specialists, who will not be those at present
advising the government on CFS. They should be drawn from
those who have the necessary knowledge, expertise and
experience of examining and investigating ME patients and who
can point to the infectious origin of ME, its known epidemiology,
history of epidemics, known biomedical research profile,
testable pathological changes, post mortem findings and other
robust scientific evidence.

We respectfully submit as evidence selected quotes from the
Nightingale Definition of ME by The Nightingale Research
Foundation, Ottawa, Canada, with which our Executive Director
Jane Colby was invited to assist. The Nightingale Definition will
shortly be available in full.

The expertise and knowledge that NICE needs on ME is
available. The Trust is dismayed that NICE has allowed such a
narrow perspective to inform such vital work and requests that it
reconsider the whole guideline in the light of our submission, our
new evidence, and that of other patient organisations.


ME is a clearly defined disease process. CFS by definition has
always been a syndrome. At one of the meetings held to
determine the 1994 CDC definition of CFS [.] Dr. K Fukuda
stated that numerous ME epidemics  -* he cited the Los Angeles
County Hospital epidemic of 1934, the Akureyri outbreak of
1947-48 and the 1955-58 Royal Free Hospitals epidemics *-
were definitely not CFS epidemics. Dr. Fukuda was correct. [.]

Primary ME is an acute onset biphasic infectious disease
process, where there is always a measurable and persistent
diffuse vascular injury of the CNS in both the acute and chronic
phases. Primary ME is associated with immune and other
pathologies. [.]

Primary ME is a chronic disabling, acute onset biphasic
infectious disease process affecting both children and adults.
There are both central and peripheral aspects to this illness. [.]

Primary Infection Phase: The first phase is an epidemic or
endemic infectious disease generally with an incubation period
of 3 to 7 days; in most, but not all cases, an infection or
infectious process is evident. (See Clinical and Scientific Basis
of M.E./CFS, Hyde B, pps.124-126)

Secondary Chronic Phase: The second and chronic phase
follows closely on the first phase, usually within two to seven
days; it is characterized by a measurable diffuse change in the
function of the Central Nervous System. This second phase is
the persisting disease that most characterizes ME [.]

Extent of Injury

Type 1: One side of the cortex is involved. Those patients
labeled as 1A have the best chance of recovery.

Type 2: Both sides of the cortex are involved. These patients
have the least chance of spontaneous recovery.

Type 3: Both sides of the cortex, and either one or all of the
following: posterior chamber organs (the pons and cerebellum),
limbic system, the sub-cortical and brainstem structures are
involved. Type 3B are the most severely affected patients and
the most likely to be progressive or demonstrate little or no
improvement with time.

Degree of injury

Type A: Anatomical integrity is largely maintained in the Brain
SPECT scan.

Type B: Anatomical integrity is not visible in the CNS SPECT

Type 3B are some of the most severely and chronically injured
patients. [.]

What is new and different about the Nightingale ME Definition is
the following:

A Testable Definition: The definition is set out in both a clinical
diagnostic and scientifically testable fashion. This will allow the
physician both an early diagnostic bedside or office
understanding of the illness and a scientific and technological
method to investigate and confirm the diagnosis. [.]


The Nightingale Definition lists the following:

      - Testable Neuropsychological Changes

      - Testable Major Sleep Dysfunction

      - Testable Muscle Dysfunction

      - Testable Vascular Dysfunction. POTS; Cardiac
      Irregularity; Raynaud's Disease; Circulating
      Blood Volume Decrease; Bowel Dysfunction;
      Ehlers-Danlos Syndromes Group; Persantine
      Effect in ME Patients; ME Associated Clotting

      - Testable Endocrine Dysfunction: This feature
      is common and tends to be a late appearance. It
      is most obvious in: Pituitary-Thyroid Axis;
      Pituitary-Adrenal Axis Changes;
      Pituitary-Ovarian Axis Changes; Bladder
      Dysfunction Changes

In the Nightingale Definition of ME, more than 30 physicians are
listed who have to varying degrees also noted the historical and
the more recent investigational findings. We recommend this
definition to NICE.


The Trust has been working co-operatively with the ME
Association regarding children with ME at their invitation. We
endorse the critique of the NICE guideline by the ME
Association in its submission.

The Trust agrees with the stance taken by the 25% Group on this

The Trust agrees with the view of the Edinburgh MESH group
and others that patient evidence has not been accorded
sufficient weight or respect. This is entirely at variance with the
government's own Expert Patient scheme and its aim to involve
the Patient Voice.

The Trust is in sympathy with virtually all comments that we have
read from ME Support Groups and group consortia around the
UK. Some responses have included a plethora of detail with
research references. We would emphasise that when virtually
every patient group and support organisation in the country
explains in a respectful and well-defined way that these
guidelines are not fit for purpose, NICE would be well advised to
take full cognisance of these views.

In the Trust's opinion there is a lack of information about
children's needs in the guideline and in some ways they are very
badly served by it; see our points below, which should be taken
to refer to children and young people with ME rather than the
broader chronic fatigue.

NICE appears to suggest that young people aged 16-19 may
choose to remain under the care of a paediatrician rather than
transfer to adult services. It is unclear if NICE is suggesting an
increase in paediatricians' caseloads and a change in the usual
system of transfer at 16.

NICE has used the RCPCH guideline to inform this guideline
and so has perpetuated some of its mistakes rather than
re-considering the issues afresh with new advisers.

P34 1.4 1.3
On the severely affected, it is suggested that Graded Exercise
Therapy may be appropriate 'to help develop their physical
capacity and functioning'. This perception of exercise as being
able to 'do the recovery' to the person, is at variance with patient
experience, and the clinical experience of other physicians not
asked to advise NICE, who maintain that supporting the body's
natural recovery process, so that it is able to do more when
healing occurs (the same principle as applying a plaster to
broken bone) is safer and more effective than trying to force the
pace of healing. Capacity extends naturally as healing takes

In the Trust's opinion, GET should only be considered as an
option when a person is sufficiently well into the recovery phase
and is much stronger and able to start increasing activity without
making themselves worse. Severely affected children are
commonly pressurised to increase activity inappropriately and
we have seen terrible relapses as a result, with memory loss,
paralysis, return to the stage of tube feeding due to inability to
swallow. Such relapses can be very long term. One young
person of 26 reported still being unable to walk 11 years after
receiving such treatment in his teens. Referring to those
advocating GET, he wrote to us: 'They must be stopped'. In more
than one instance physicians have openly admitted that GET has
caused harm and apologised to the family. We do not wish to
see further examples of such treatment being meted out to
severely affected children.

We can see no specific warning such as that set out in Chapter
5 of the CMO's Working Group Report against mistakenly
attributing cases of ME to Munchausen's Syndrome by Proxy or
FII (Fabricated Induced Illness).

This is necessary due to the still persistent mislabelling of
families as either neglecting or abusing their children. It seems
particularly prevalent in our home county of Essex and our 2005
report 'Our Needs Our Lives' showed an increase rather than a
decrease in such problems. We have submitted evidence at the
invitation of the parliamentary group that is calling for the
withdrawal of the guidelines on MSBP and FII issued in 2002 by
the Department of Health under the title 'Safeguarding Children
in Whom Illness is Fabricated or Induced'. These same 2002
guidelines are incorporated without amendment at Section 6.6
of the 2006 DfES initiative 'Working Together - A Guide to
Interagency Working'.

In Chapter 5 of the CMO's Working Group Report, it states:

a) In cases of CFS/ME, evidence clearly suggestive of harm
should be obtained before convening child protection
conferences or initiating care proceedings in a family court

b) Neither the fact of a child or young person having unexplained
symptoms nor the exercising of selective choice about treatment
or education constitutes evidence of abuse.

It is frequently Local Education Authorities and Social Services
who report the family because the child cannot get to school in
the normal way. Rather than providing them with their legal
entitlement to suitable education and abiding by Disability
Discrimination legislation, they institute inappropriate
proceedings which could be stopped and resolved by well
informed physicians. NICE should assist them in this. For further
such evidence we refer you to NMEC (National ME Centre,
Harold Wood, Essex).

We would refer NICE to the short summary document 'Children
and Young People: The Key Points', located at
www.tymestrust.org/pdfs/keypoints.pdf which lists statements
from the CMO's Working Group Report that we consider
particularly relevant for professionals working with children.
Points such as these need to be clearly incorporated into the
NICE guideline.


There are some helpful statements in the NICE guideline which
we wish to recognise. One is that healthcare professionals for
both adults and children should have the appropriate skills and
expertise - but who is training them? If the training simply
perpetuates the same inappropriate psychologically based
attitudes to ME, then this worthy aim will produce harm rather
than good.

The statement that paediatricians should follow advice from the
Department for Education and Skills on education for sick
children is helpful. However, the publication 'Access to
Education for Children and Young People with Medical Needs'
by the DfES contains ambiguities that have been the subject of
personal discussion between Parliamentary Under-Secretary of
State for Schools, Lord Adonis and the Young ME Sufferers
Trust. Lord Adonis has, as a result, issued a clarification to state
that a GP's support and advice eg for tuition in the home, is
valid. A sick child must legally be offered education by other
means after 15 days of being unable to attend school through
illness. Almost no family will see a paediatrician within this
timescale. This should be reflected by NICE by referring to the
usefulness of supportive advice from GPs as well as consultants
in its guidance. Many GPs do not feel able to give such support
at the moment or are ignored when they do.

Sharing supportive information with schools and making
recommendations for adaptations to education are both worthy
aims but this is only helpful when such information takes full
account of the young person's needs, includes full recognition of
the disabilities inherent in ME, and recognises that in the 21st
century new forms of education are extremely useful to children
with ME, such as interactive online education. The Trust works
with Nisai Education to provide one such system, which is
producing far better educational grades than conventional
methods of education for children with ME. School is not a social
club and it is perfectly possible to provide for social contact
separately. The child has educational rights which are effectively
contravened by physicians insisting on school attendance
regardless of academic results. There is an increased tendency
for medical studies to use attendance at school as a measure of
recovery. School attendance is not a suitable measure of
recovery in itself; studies should take account of whether or not
the young person's academic achievement is on a par with that
of their healthy peers as a result of going back into school.

The recommendation to liaise with Disability advisers is

The recommendation to consider the provision of equipment
and aids such as wheelchairs, blue badges and stair lifts is
particularly welcome as it is not only helpful in itself, it contradicts
the view prevalent amongst many physicians that such provision
will not facilitate recovery but will instead perpetuate disability.


The guideline uses compassionate language in many places
and we do feel that overall the intention is to help patients rather
than perpetuate and propagate dogma based on opinion rather
than sound evidence. However, the selective use of 'evidence'
does just that; it does perpetuate ill-informed opinion and dogma
and takes far too much account of studies whose subjects plainly
did not have ME at all.

Compassionate language in itself is not enough. It is the
message that is the most important thing, and the message of
this guideline is that many people with ME do not prioritise
getting better. This is not only untrue, it is a grave insult to those
who are already doing their utmost to cope with one of the most
disabling illnesses in existence.

Our bottom line is that this guidance should have emphasised
helping patients towards autonomy and supported
self-management. It does not fulfil this purpose and its sidelining
of the specific needs of the young do them a great disservice.
We recommend NICE to read Chapter 5 of the CMO's Working
Group Report in full.

In the Trust's opinion, this guideline needs a complete rewrite,
involving a more balanced group of advisers including full patient
representation. If it  were published as it stands, the political
fallout and the personal fallout  for patients with ME would be

Jane Colby
Executive Director
The Young ME Sufferers Trust
PO Box 4347
Stock Ingatestone
Essex CM4 9TE
Tel 01245 401080

[Return to top]


Date:    Thu, 30 Nov 2006 21:15:07 +0100
From:    Jan van Roijen <j.van.roijen@xxxxx.xx>
Subject: act,med: Vested Interest & Behavioral Interventions in CFS


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From:  DEnlander@xxx.xxx

from Wikipedia online encyclopedia

''Behavioral Interventions in CFS'':  Dr Enlander an internist in
New York states that Behavioral interventions are proposed
usually by psychiatrists who have a vested interest.

A questionable study published in the Journal of the Royal
Society of Medicine has found that behavioural interventions
including cognitive behavioural therapy and graded exercise
therapy are effective treatments for chronic fatigue syndrome in
adults. The research was performed by psychiatrists.

[Return to top]


Date:    Fri, 1 Dec 2006 12:56:40 +0100
From:    "Dr. Marc-Alexander Fluks" <fluks@xxx.xx>
Subject: RES: e-Medicine classification for CFS

The e-Medicine classification of diseases is an online alternative
for the ICD of the WHO.

* e-Medicine classification of CFS: an infectious disease,
* e-Medicine classification for CFS: med/3392
* e-Medicine 'Continuing Medical Education' (CME) for CFS,
* e-Medicine CFS papers (today: 880 hits),

[Return to top]


Date:    Fri, 1 Dec 2006 11:38:20 -0500
From:    "LK Woodruff <lkw777@xxxxx.xx>" via Co-Cure Moderators
Subject: MED: Understanding M.E. and CFS - Dr. Byron Hyde

 From the guy who wrote the  'bible'. LKW

Understanding M.E. and CFS
     - Dr. Byron Hyde


If a patient or a family member has tried to search the internet for an
understanding of either Myalgic Encephalomyelitis (M.E.) or Chronic Fatigue
Syndrome (CFS), they will have been overwhelmed by the multitude of
technical descriptions and the numerous overlapping medical conditions. Both
M.E. and CFS represent a complex, multi-system group of afflictions,
adversely affecting the brain, heart, neuro-endocrine, immune and
circulatory systems in our bodies and are two separate illnesses. At times,
this has led to M.E. and CFS symptoms being confused with the symptoms for
neurasthenia, multiple chemical sensitivities, fibromyalgia syndrome and
chronic mononucleosis.

~~M. E. has a clearly defined disease process while CFS by definition has
always been a syndrome.~~

***In light of this state of affairs, the Nightingale Research Foundation
has updated its definition of M.E.1 (pdf format) , effective November

There have been many attempts to define CFS, some described in our textbook,
The Clinical and Scientific Basis of Myalgic Encephalomyelitis / Chronic
Fatigue Syndrome. The Canadian Encyclopedia online also has a useful one.

The US Centers for Disease Control and Prevention (CDC) definitions of CFS
started with the 1988 CDC definition that was then rolled over to an even
more complex 1994 definition that was then corrected and corrected again. It
is difficult to say where it all starts and where it stops. These CFS
definitions have multiplied beyond the two CDC definitions and now include
the Oxford, England definitions of CFS (there are two in this definition),
the Australian definitions, and the more recent Canadian definition that
talks of M.E. / CFS as though they were the same illness. ~~They are not.~~

The Complexities of Diagnosis

In 2003, Dr. Byron Hyde completed a chapter for L. A. Jason, P. A. Fennell
and R. R. Taylor for their book Handbook of Chronic Fatigue Syndrome, John
Wiley and Sons Inc., Hoboken N.J., titled "The Complexities of Diagnosis"1
(pdf format), Chapter 3. This chapter includes the following definition of
"The physician and patient alike should remember that CFS is not a disease.
It is a chronic fatigue state where the one essential characteristic of M.E.
is acquired Central Nervous System (CNS) dysfunction, that of CFS is
primarily chronic fatigue.

By assumption, this CFS 'fatigue' can be acquired abruptly or gradually.
Secondary symptoms and signs were then added to this primary fatigue
anomaly. None of these secondary symptoms is individually essential for the
definition and few are scientifically testable. Despite the list of signs
and symptoms and test exclusions in these definitions, patients who conform
to any of the CDC, Oxford, Australian and Canadian CFS definitions may still
have an undiagnosed major illness, certain of which are potentially

Although the authors of these definitions have repeatedly stated that they
are defining a syndrome and not a specific disease, patient, physician, and
insurer alike have tended to treat this syndrome as a specific disease or
illness, with at times a potentially specific treatment and a specific
outcome. This has resulted in much confusion, and many physicians are now
diagnosing CFS as though it were a specific illness. They either refer the
patient to pharmaceutical, psychiatric, psychological, or social treatment
or simply say: "you have CFS and nothing can be done about it". The CFS
definitions have another curiosity. If in any CFS patient, any major organ
or system injury or disease is discovered, the patient is removed from the
definition. The CFS definitions were written in such a manner that CFS
becomes like a desert mirage: The closer you approach, the faster it
disappears and the more problematic it becomes."

Definition Precepts

Here are some of the essential definition precepts that we believe are
important in being able to diagnose accurately either M.E. or CFS or any
chronically ill patients group.

A working case clinical definition must be short, clear and testable.

The patient and their illness or illnesses must be part of an integrated
system and neither the patient's patho-physiology nor their illness can be
understood without a concise knowledge of their integrated
pathophysiological systems.

A statistically significant group of patients who have M.E. and CFS type
illnesses must be subjected to a complete personal and family history to map
the genetic and historical causes of their illnesses.

Accordingly, the patient's illness can only be understood if a complete
total body mapping is performed on all systems and organs. The mammalian and
animal bodies are an integrated physiological mechanism and when one major
system change occurs, many physiological systems are liable to shift.

In the past it has been facile to pose psychiatric diagnoses on M.E. and CFS
patients since psychiatric diagnoses cannot be subjected to scientific
examination. Psychiatrists rarely actually examine patients and almost never
do an integrated patho-physiological patient investigation of the patient's
organs and systems. Nor have most psychiatrists been of any help in
diagnosing M.E. and CFS patients except to the insurance industry. In the 75
years since the first major M.E. and CFS epidemic struck the Los Angeles
County General Hospital in 1934, no psychiatric treatment has proven
significantly effective in treating the M.E. and CFS group of patients and
restoring them to health. ~~This is understandable since neither represents
a psychiatric disorder.~~

Effective treatment of the M.E. and CFS group of patients depends upon
precisely defining the organ and system pathologies and learning how to
treat these patho-physiological conditions.

M.E. and the CFS group of illnesses are chronic illnesses. For too long
physicians have been considering chronic diseases and chronically ill
patients as they would acute short-term illnesses. We believe this is an
error and we direct those interested to our chapter on diagnosis. Relatively
young chronically ill patients, often do not have a disease process, they
often have many disease processes.


[Return to top]


Date:    Fri, 1 Dec 2006 18:40:59 +0100
From:    Jan van Roijen <j.van.roijen@xxxxx.xx>
Subject: med: The Nightingale Definition of ME


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Thanks to LaVonne K Woodruff - lkw777@xxxxx.xxx


The Nightingale Definition of Myalgic Encephalomyelitis (M.E.)


Since the Nightingale Research Foundation's publication in 1992 of its
textbook, The Clinical and Scientific Basis of Myalgic Encephalomyelitis /
Chronic Fatigue Syndrome, there has been a tendency by some individuals
and organizations to assume that M.E. and CFS are the same illness. Over
the course of two International Association of Chronic Fatigue Syndrome
(IACFS, formerly the American Association of CFS) conferences, there
have been suggestions that the name CFS be changed to M.E., while
retaining the CFS definitions as a basis for such change. This does not
seem to me to be a useful initiative: it would simply add credence to the
mistaken assumption that M.E. and CFS represent the same disease
processes. They do not.

M.E. is a clearly defined disease process. CFS by definition has always
been a syndrome

At one of the meetings held to determine the 1994 U.S. Centers for Disease
Control and Prevention (CDC) definition of CFS, in response to my question
from the floor, Dr. Keiji Fukuda stated that numerous M.E. epidemics—he
cited the Los Angeles County Hospital epidemic of 1934, the Akureyri
outbreak of 1947-48 and the 1955-58 Royal Free Hospitals epidemics--
were definitely not CFS epidemics. Dr. Fukuda was correct.

The Psychiatric Label

Unfortunately many physicians and some senior persons in governments,
including Great Britain, Norway and to a lesser degree the USA and
Canada treat CFS as a psychiatric illness. This view has been arrived by
some physician's readings of the CFS definitions from CDC. Indeed,
despite clear signals in the 1994 CDC definition that CFS is not a
psychiatric disease, each of the CDC definitions and their addenda
referring to CFS remain open to interpretation as a psychiatric rather than a
physical illness. This is not a view to which I subscribe. It is the CFS
definitions themselves that give rise to this inaccuracy. Consider the

(a) What other physical disease definitions essentially state that if you
discover the patient has any physical injury or disease, then the patient does
not have the illness CFS? In other words if you have CFS then it does not
result in or cause any major illness. What else could CFS then be but any
number of various psychiatric, social, hysterical or mendacious

(b) The various CDC administrations dealing with the subject have clearly
stated that CFS is a physical, not a psychiatric disease. However, is there
any other definition of any physical disease that is not provable by
and clinical tests? Only psychiatric diseases are not clearly verifiable by
physical and technological tests.

(c) What other physical disease definition requires a six month waiting
period before the illness can be diagnosed? Any physician knows that to
treat a disease adequately you have to be able to define the disease at its
onset and treat it immediately in order to prevent chronic complications from
arising. There are simply no other disease definitions that have ever been
assembled similar to the CFS definitions.

(d) If you are still not convinced, check the Internet for the Diagnostic and
Statistical Manual of Mental Disorder definition of: DSMIII Somatization
Disorder. You will find that there is little substantial difference
to distinguish
the DSMIII definition from the 1988 and 1994 CDC definitions of CFS. It is
difficult to believe that the CDC medical bureaucracy is not aware of this
similarity. It is thus understandable why the insurance industry, as well as
some psychiatrists and physicians, have simply concluded that CFS is
somatization disorder.

I believe it essential to define clearly Myalgic Encephalomyelitis. That is
what the Nightingale definition of M.E. sets out to do. The
definition is based
upon two criteria:

(a) The excellent scientific work of respected physicians and scientists who
investigated the various M.E. epidemics

(b) Our Foundation's modern scientific testing techniques and the
knowledge resulting from examining thousands of M.E. patients using these

The proposed M.E. definition is designed to improve early diagnosis and
treatment for the tens of thousands of patients stricken with M.E. It is not a
new definition of CFS nor should it be conceived as a rewording of any
previous CFS definition.

What follows is the primary M.E. definition for adults.

The Nightingale Definition of Myalgic Encephalomyelitis (M.E.)

Primary M.E. is an acute onset biphasic infectious disease process, where
there is always a measurable and persistent diffuse vascular injury of the
Central Nervous System in both the acute and chronic phases. Primary M.E.
is associated with immune and other pathologies.

Primary M.E. is a chronic disabling, acute onset biphasic infectious disease
process affecting both children and adults. There are both central and
peripheral aspects to this illness.

A: The Central Nervous System (CNS) symptoms, as well as the clinical and
technological abnormalities, are caused by a diffuse and measurable injury
to the vascular system of the Central Nervous System. These changes in the
organization of the CNS are caused by a combined infectious and
immunological injury and their resulting effect on CNS metabolism and
control mechanisms. Much of the variability observed in an M.E. patient's
illness is due to the degree and extent of the CNS injury and the
ability of the
patient to recover from these injuries.

B: A significant number of the initial and long-term peripheral or body
symptoms, as well as clinical and technological body abnormalities in the
M.E. patient, are caused by variable changes in the peripheral and CNS
vascular system. The vascular system is perhaps the largest of the body's
organs and both its normal and pathological functions are in direct
relationship to CNS and peripheral vascular health or injury, to CNS control
mechanisms and to the difficulty of the peripheral vascular system and
organs to respond to CNS neuro-endocrine and other chemical and
neurological stimuli in a predictable homeostatic fashion.

C: When pain syndromes associated with M.E. occur, they are due to a
combined injury of (i) the posterior spinal cord and / or posterior
root ganglia
and appendages, (ii) patho-physiological peripheral vascular changes, and
(iii) CNS pain reception homeostasis mechanisms.

Depending upon the degree and extent of the ongoing CNS and peripheral
vascular injuries, these patho-physiological changes in turn may give rise to
both transient and in many cases permanent systemic organ changes in the

As with any illness, the diagnostic criteria of M.E. are divided into two

(a) The clinical features and history of the ill patient that alert
the physician to
the initial diagnosis

(b) The technological examinations that confirm to the physician proof of the

Clinical Features

The clinical features of Myalgic Encephalomyelitis are consistent with the
following characteristics that can easily be documented by the physician.

1. M.E. is an acute onset biphasic epidemic or endemic infectious disease:
Both Epidemic and Non-Epidemic cases are often preceded by a series of
repeated minor infections in a previously well patient that would suggest
either a vulnerable immune system, or an immune system subject to
overwhelming stressors such as: (a) repetitive contact with a large number
of infectious persons,

(b) unusually long hours of exhausting physical and / or intellectual
work, (c)
physical traumas, (d) immediate past immunizations, (e) epidemic disease
cases whose onset and periodicity appear to occur cyclically in a
susceptible population, (f) the effect of travel, as in exposure to a
new subset
of virulent infections, or (g) the effects of starvation diets. (It
should be noted
that subsets c, d, e, f and g are all stressors associated with decreased
immune adaptability plus an associated infection with an appropriate
neurovascular infectious virus or other infectious agents. This may be due
either to an immediate preexisting infectious disease or to a closely
following infection, either of which may or may not be recognized.)

2. Primary Infection Phase: The first phase is an epidemic or endemic
infectious disease generally with an incubation period of three to seven
days; in most, but not all cases, an infection or infectious process
is evident.
(See B. Hyde and A Jain, Clinical and Scientific Basis of M.E./CFS,
Chapter 13, Nightingale Research Foundation, Ottawa, Canada, pp.

3. Secondary Chronic Phase: The second and chronic phase follows closely
on the first phase, usually within two to seven days; it is characterized by a

diffuse change in the function of the Central Nervous System. This second
phase is the persisting disease that most characterizes M.E.

4. The Presence or Absence of Various Pain Syndromes is highly variable:
The pain syndromes associated with the acute and chronic phases of M.E.
may be described as Early and Late findings. Early Findings: (a) severe
headaches of a type never previously experienced; (b) these are often
associated with neck rigidity and occipital pain; (c) retro-orbital
eye pain; (d)
migratory muscle and arthralgia pain; (e) cutaneous hypersensitivity. Late
Findings: (f) fibromyalgialike pain syndromes. When occurring, these
various pain syndromes may include fibromyalgia-like pain syndromes.
Many of the pain features tend to decrease over time but can be activated or
increased by a wide range of external and chemical stressors. (See Clinical
and Scientific Basis of M.E./CFS, Chapter 5, pp. 58-62)

Testable and Non-testable Criteria:

The technological tests listed below can be used to (a) confirm the clinical
diagnosis of Myalgic Encephalomyelitis and (b) to some degree gauge its
severity and probability of persistence. The second and chronic phase that
clearly defines M.E. is characterized by various measurable and clinical
dysfunctions of the cortical and/or sub-cortical brain structures.

5. Diffuse Brain Injury Observed on Brain SPECT: If the patient's illness is
not measurable using a dedicated brain SPECT scan such as a Picker
3000 or equivalent, then the patient does not have M.E. For legal purposes,
these changes may be confirmed by PET brain scans with appropriate
software and / or QEEG. These changes can be roughly characterized as to
severity and probable chronicity using the following two scales: A: extent of
injury and B: degree of injury of CNS vascular function.

Extent of Injury

Type 1: One side of the cortex is involved. Those patients labeled as 1A
have the best chance of recovery.

Type 2: Both sides of the cortex are involved. These patients have the least
chance of spontaneous recovery.

Type 3: Both sides of the cortex, and either one or all of the following:
posterior chamber organs, (the pons and cerebellum), limbic system, the
sub-cortical and brainstem structures are involved. Type 3B are the most
severely affected patients and the most likely to be progressive or
demonstrate little or no improvement with time

Degree of injury

Type A: Anatomical integrity is largely maintained in the Brain SPECT scan.

Type B: Anatomical integrity is not visible in the CNS SPECT scan. Type 3B
are some of the most severely and chronically injured patients.

6. Testable Neuropsychological Changes: There are neuropsychological
changes that are measurable and demonstrate short-term memory loss,
cognitive dysfunctions, increased irritability, confusion, and perceptual
difficulties. There is usually rapid decrease in these functions after any
physical or mental activity. Neuropsychological changes must be measured
in relation to estimates of prior achievement. This feature may improve over
a period of years in patients with adequate financial and social support and
can be made worse by chronic stressors. The neurophysiological changes
are those observed by a qualified neuropsychologist with experience in
examining this type of disease spectrum. (See S. Bastien in Clinical and
Scientific Basis of M.E. / CFS, Chapter 51, pp. 453-460.)

7. Testable Major Sleep Dysfunction: This can include all forms of sleep
dysfunction. All or any of the following may be present: (a) impaired sleep
efficiency, (b) significant fragmented sleep architecture, (c) movement
arousals if there is an associated pain syndrome, (d) absence of type 3 and
4 sleep, (e) abnormal REM sleep pattern (f) changes in daytime alertness
and (g) sleep reversals.

8. Testable Muscle Dysfunction: This feature may be due to vascular
dysfunction or peripheral nervous or spinal dysfunction and includes both
pain and rapid loss of strength of muscle function after moderate physical or
mental activity. This feature tends to improve over a period of years but
many patients frequently remain permanently vulnerable to new disease
episodes. Few centres are equipped or funded to make these

9. Testable Vascular Dysfunction: This is the most obvious set of
dysfunctions when looked for and is probably the cause behind a significant
number of the above complaints. As noted, the primary vascular change is
seen in abnormal SPECT scans and clinically most evident in patients with:

a. POTS: severe postural orthostatic tachycardia syndrome. Note: This
group can be confused with diabetes insipidus due to the fact that they may
have polydipsia from their attempt to increase their circulating blood volume
by consuming large amounts of fluids. This group can be verified by the
absence of pituitary adenoma or pathology and the fact that they can sleep
through the night without waking to drink fluids.

b. Cardiac Irregularity: on minor positional changes or after minor physical
activity, including inability of the heart to increase or decrease in
speed and
pump volume in response to increase or decrease in physical activity.

c. Raynaud's Disease: vasoconstriction, blanching, coldness and pain of
extremities. This is in part the cause for temperature dysfunctions seen in

d. Circulating Blood Volume Decrease: this is a nuclear medicine test in
which the circulating red blood cell levels can fall to below 50%, preventing
adequate oxygenation to the brain, gut and muscles. This is undoubtedly a
subcortical dysregulation. It is associated with serum and total blood volume
measurements. Note: Body servomechanisms are genetically designed so
that blood flow and oxygen to the heart are always protected. Thus blood
flow to organs not necessary for short-term survival, such as the brain, the
gut and muscles, can be temporarily decreased. This of course gives rise to
many of the M.E. symptoms.

e. Bowel Dysfunction: vascular dysfunction may be the most significant
causal basis of the multiple bowel dysfunctions occurring in M.E.

f. Ehlers-Danlos Syndromes Group: this is a group of illnesses with a
genetic predisposition to M.E. or M.E.-like illness. In fact it probably
represents a spectrum of illnesses that start with (i) Hyper-Reflexia
Syndrome, moving through any of the (ii) various Ehlers-Danlos Syndromes
and climaxing in (iii) Marfan Syndrome where there tends to be early death if
the aortic and cardiac changes are not repaired. Ehlers- Danlos Syndromes
can go undetected until what appears to be an infectious switch is turned on,
usually in late teens to early thirties. Briefly, patients over the
age of 16 who
can (i) touch their nose with their tongue, (ii) touch their forearm with the
thumb of the same extremity, (iii) touch the floor readily with the full palm
should be considered suspect for further examination. See S.I. Magalini,
S.C. Magalini, Dictionary of Medical Syndromes, pp. 251-252,
Lippincott-Raven Publishers, Philadelphia, 4th Edition, 1997.

g. Persantine Effect in M.E. Patients: Persantine is a chemical
manufactured by Boehringer Ingelheim. It is employed to perform chemical
cardiac stress testing when a patient cannot exercise sufficiently to stress
the heart. It is a particularly safe medication but when employed with many
M.E. patients it can cause severe muscle pain over the extremities and
entire musculature. Normally this can be reversed by injection of an antidote
but this does not always work in M.E. patients. Severe pain and fatigue can
be intolerable and persist for minutes to days in some M.E. patients
following persantine use. Persantine works by dilating both peripheral and
cardiac blood vessels and causing the heart rate to increase as in a POTS
patient. Obviously one major pain and fatigue factor in M.E. patients is
caused by abnormal dilatation of peripheral blood vessels. To my
knowledge, no testing of M.E. patients with persantine has ever been
published by Boehringer Ingelheim or others. It is one of the reasons I
believe that pain syndromes in M.E. patients are due to a pathological
vascular physiology.

h. M.E. Associated Clotting Defects: M.E. represents both a vasculitis and a
central and peripheral change in vascular physiology. All such vascular
illnesses should be potentially treatable. We do not yet know how to treat the
(i) genetic forms of vasculitis and vascular patho-physiology mentioned
here, nor (ii) the probable viral triggered genetic vascular pathologies also
mentioned. Nor do we know how to treat those (iii) centrally caused injuries
causing the circulating blood volume defects that are demonstrated when
we do the "nuclear medicine circulating blood volume tests. It is important to
do this test on all patients. POTS is poorly treatable and more often success
in treatment presently escapes physicians' ability. Eventually, I have no
doubt that these will be treatable causes of M.E. type disease. However
there is a significant group of M.E. patients who are ill due to a treatable
form of vasculitis and can be treated if the physician takes the time to
diagnose the subgroup. These patients are the clotting defect patients.
Some of these clotting defects are genetic and some appear to be genetic
with an age or viral switching mechanism; although they may develop in
childhood, they are more frequently noted well after puberty and before the
age of 40. Many of these patients can be diagnosed by the following tests:
(1) Serum viscosity test, (2) Antiphospholipid Ab., (3) Protein C defects, (4)
Protein S defects, (5) Factor V Leiden defect, to name the most common
that we have uncovered. However, there are others for which we also test.
These conditions are all potentially treatable and when treated will allow the
patient to return to normal range of activities (e.g. school, career, etc).

10. Testable Endocrine Dysfunction: This feature is common and tends to
be a late appearance. It is most obvious in:

a. Pituitary-Thyroid Axis: Changes in serum TSH, FT3, FT4, Microsomal
Ab., PTH, calcium and phosphorous rarely occur until several years after
illness onset. This can be followed by ultrasound of the thyroid gland, where
a steady shrinking of the thyroid gland may occur in some patients with or
without the development of non-serum positive Hashimoto's thyroiditis (a
seeming contradiction in terms) and a significant increase in thyroid
malignancy. In cases of thyroid wasting, serum positive changes tend to
occur only after years and often not until the thyroid gland shrinks from the
normal 13 to 21 cc. volume in an average adult female and 15 to 23 cc.
volume in male patients to below a volume of 6 cc. (Mayo Clinic averages).
Serum analysis of M.E. patients for thyroid pathology is simply not
adequate. Repeat thyroid ultrasound must be performed for all M.E. patients
to ascertain presence of dystrophic changes. It is also inadequate simply to
accept the radiologist's report of a normal thyroid. The volume of each lobe
and its homogenicity must be requested and documented.

The following changes, while uncommon, may also be related to an M.E.
disease process:

b. Pituitary-Adrenal Axis Changes: where changes and findings are

c. Pituitary-Ovarian Axis Changes

d. Bladder Dysfunction Changes: This dysfunction occurs frequently in the
early and in chronic disease in some people. In some instances this may be
due to a form of diabetes insipidus, in other cases it is related to POTS type
illness where the patient is compensating for an inability to
maintain vascular
pressure by attempting to increase fluid volume. In other cases this may be
due to interstitial cystitis or a form of polio-type-bladder
particularly if the
cause of the individual disease is an enterovirus. Dr. John Richardson also
associated this finding with adrenal dysfunction that he measured.


To various degrees all of the above historic findings have been observed
and discussed by Doctors Alexander Gilliam, Bjorn Sigurdsson, Alberto
Marinacci, Andrew Lachlan Wallis, A Melvin Ramsay (Elizabeth Dowsett
who assisted in much of his later work), John Richardson, Elizabeth Bell,
Alexis Shelokov, David C Poskanzer, W.H. Lyle, Sir E. Donald Acheson,
Louis Leon-Sotomayor, J. Gordon Parish and many others.

In varying degrees all of the following physicians have also noted the above
historical and the more recent investigational findings. They include
alphabetically, Doctors Peter Behan, David Bell, Dedra Buchwald, Paul
Cheney, Jay Goldstein, Seymour Grufferman, Anthony L Komaroff, Russell
Lane, Ismael Mena, Harvey Moldofsky, James Mowbray, Daniel Peterson,
Vance Spence and scores of others.

I have examined patients with M.E. since the late 1970s but only at the
urging of Dr. Charles Poser of Beth Israel Hospital at Harvard and John
Richardson in Newcastleupon- Tyne did I take up the study of these
unfortunate patients on a full time basis. The material in this
definition is the
cumulative result of my listening and interpreting the work of all of
the above
clinicians and my evaluation of over 3,000 M.E. and CFS patients since
1984. The essential concept of the indepth medical evaluation that is the
basis of my work on M.E. and CFS since 1995 was crystallized in my
discussions in Seattle Washington State in 2002 with Dr. Leonard A. Jason,
Patricia A. Fennell and Renee R. Taylor. This discussion was set down as
Chapter 3, "The Complexities of Diagnosis", in their book, The Handbook of
Chronic Fatigue Syndrome, John Wiley and Sons, Hoboken, New Jersey,
2003. I would also like to thank Elizabeth Dowsett and Jane Colby whose
work with children in the UK as well as their advice have been instrumental
in this definition. I must also thank each and every one of the members of
John Richardson's Newcastle Research Group who have provided me with
so much valuable information over the years and who have all supported my
continued investigations of M.E. patients.

What is new and different about the Nightingale M.E. definition?

A: A Testable Definition

The definition is set out in both a clinical diagnostic and scientifically
testable fashion. This will allow the physician both an early diagnostic
bedside or office understanding of the illness and a scientific and
technological method to investigate and confirm the diagnosis. It is well
known by all serious physicians that in order to assist the patient
in a partial
or full recovery the illness must be (a) prevented from occurring by either
immunization or understanding and avoiding the causes, (b) diagnosed and
treated immediately following onset. The Nightingale Definition assists the
physician in diagnosis and early treatment.

B: A Vascular Pathophysiology

The subject of vascular pathology is not new. The fact of the
children dying of
a Parkinsonian-like vascular injury to the basal ganglia in Iceland during the
Akureyri Epidemic is an obvious indication of the CNS vascular effects.
Vasculitis has been well documented by Dr. E. Ryll in his description of the
epidemic in the San Juan Mercy, Sacramento California Hospital in 1975.
He described this M.E. epidemic as an epidemic vasculitis. In the late
1980s Drs. Jay Goldstein and Ismael Mena confirmed and proved this initial
description by examining the changed brain microcirculation using brain
SPECT imaging in M.E. patients. Following my over twenty years of
examining M.E. and CFS patients and sixteen years of subjecting the M.E.
and CFS patients to brain imaging techniques suggested by Goldstein and
Mena, it has become obvious to me that we are dealing with both a
vasculitis and a change in vascular physiology.

Numerous other physicians have supported this finding. Dr. David Bell, who
rediscovered the work of Dr. David Streeten and his book, Orthostatic
Disorders of the Circulation: Mechanisms, Manifestations and Treatment,
New York: Plenum Medical, 1986, advanced this understanding of M.E. The
work of Dr. Vance Spence and his colleagues in Scotland have started to
nail this CNS-vascular relationship down even further with a series of major
research papers. The recent interpretation of the cause of Multiple Sclerosis
(MS) as an injury of the microvasculization causing the injury of the schwann
cells that in turn causes the demyelination injuries of MS has been added to
that of paralytic poliomyelitis as an essential vascular injury. Paralytic
poliomyelitis was thought to be a primary injury to the anterior horn cells of
the spinal cord but is now recognized as a vasculitis injuring the circulation
to the anterior horn cells. Poliomyelitis is generally a non-progressive,
specific site injury, although post-polio syndrome has challenged that belief.
MS is a recurrent more fulminant physiological vascular injury.

M.E. appears to be in this same family of diseases as paralytic polio and
MS. M.E. is definitely less fulminant than MS but more generalized. M.E. is
less fulminant but more generalized than poliomyelitis. This relationship of
M.E.-like illness to poliomyelitis is not new and is of course the reason that
Alexander Gilliam, in his analysis of the Los Angeles County General
Hospital M.E. epidemic in 1934, called M.E. atypical poliomyelitis.

C: The Lack of Mention of Fatigue

Myalgic Encephalomyelitis is not CFS. Fatigue was never a major
diagnostic criterion of Myalgic Encephalomyelitis. Fatigue, loss of stamina,
failure to recover rapidly following exposure to normal physical or
stressors occur in most if not all progressive terminal diseases and in a very
large number of chronic non-progressive or slowly progressive diseases.
Fatigue and loss of stamina are simply indications that there is something
wrong. They cannot be seriously measured, are generally subjective and do
not assist us with the diagnosis of Myalgic Encephalomyelitis or CFS or for
that matter any disease process.

D: Cause of Myalgic Encephalomyelitis

It is obvious that all cases of epidemic M.E. and all primary M.E. are
secondary to infectious / autoimmune phenomena. Many M.E. and M.E.-like
patients' illness is complicated by multiple other causes. This is why a
complete technological investigation has to be made on each chronically ill
M.E. or M.E.-like patient. Under epidemic and primary M.E. there is no
consensus as to the viral or infectious cause. Much of this lack of consensus
may be due to the non-separation of acute onset from gradual onset
patients in the M.E. and CFS groups of patients. Primary M.E. is always an
acute onset illness. Doctors A. Gilliam, A. Melvin Ramsay and Elizabeth
Dowsett, John Richardson of Newcastle-upon-Tyne, W.H. Lyle, Elizabeth
Bell of Ruckhill Hospital, James Mowbray of St Mary's and Peter Behan all
believed that the majority of primary M.E. patients fell ill
following exposure
to an enterovirus (Poliovirus, ECHO, Coxsackie and the numbered viruses
are the significant viruses in this group).

I share this belief. Unfortunately, it is very difficult to recover polio and
enteroviruses from live patients. Dr. James Mowbray developed a test that
demonstrated enterovirus infection in many M.E. patients but I do not believe
he qualified his patients by acute or gradual onset type of illness.
In my tests
in Ruckhill Hospital in Glasgow, I found confirmation of enteroviral infection
only in acute onset patients and not in any gradual onset patients. Few
physicians realize that almost all cases of poliovirus recovered from
poliomyelitis victims came from cadavers. At the very least, these
enteroviruses must be recovered from patients during their onset illness and
this has rarely been done. An exception is in the case of the
Newton-le-Willows Lancashire epidemic where Dr. W. H. Lyle's
investigation recovered ECHO enterovirus. Recent publications by Dr. J. R.
Kerr have also identified the fact that enteroviruses are one of the
most likely
causes of M.E. If this belief is correct, many if not most of the
M.E. illnesses
could be vanquished by simply adding essential enteroviral genetic material
from these enteroviruses to complement polio immunization.

I have not discussed non-infectious M.E.-type disease. Similar M.E.
phenomena can occur due to diffuse Central Nervous System injuries from
toxic chemical injury. I have seen this in police officers who have
fallen into
toxic chemical ponds in pursuit of those suspected of criminal
activity. I have
seen it in farmers, in hospital and industrial workers and in
military personnel
in contact with toxic chemicals, specifically toxic gases. I plan to explore
these in a future publication as Secondary M.E. They do have one thing in
common, and that is the diffuse CNS injury as noted on brain SPECT scans.
Often these Secondary M.E. diseases are more severe than the Primary
M.E. cases.

E: Caution One

One should be careful in applying the diagnostic criteria discussed under
the Nightingale M.E. Definition without also completing a thorough
investigation. M.E., whether we are discussing primary or secondary forms,
involves a significant diffuse injury of the Central Nervous System and an
associated injury of the Immune System. This always implies the potential
for secondary injuries or secondary disease or pathology caused by a
dysfunctional brain and dysfunctional immune system. When the immune
system is injured there is an impairment of the patient's ability to
resist the
development of malignancy or other important organ and systemic injuries.
Due to funding limitations, we have only been able to demonstrate in our
work only two characteristics of this corollary injury. The first is the high
incidence of thyroid cancer in M.E. patients. In the general public, cancer of
the thyroid occurs in 1 case per 100,000. In our studies, in the case of the
M.E. patient, thyroid cancer has an incidence of 6,000 cases per 100,000.
We have already mentioned the pervasive vascular injuries. We believe that
other pathological associations also occur. Failure to evaluate fully the M.E.
patient may result in the physician missing important secondary pathology
and possibly giving rise to patient death.

All M.E. patients as well as all chronic illness patients deserve a systematic
and total body investigation. No individual should go through life,
ill, disabled
without knowing why he is ill. Simply offering a label, whether M.E. or CFS,
without looking at the pathophysiology, is both unacceptable and potentially
dangerous both for the patient and the patient's physician.

(See "The Complexities of Diagnosis" by Byron Hyde, in the Handbook of
Chronic Fatigue Syndrome, Chapter 3)

F: Caution Two

Insurance companies regularly employ reputedly independent psychologists
who demonstrate normal neuropsychological findings. This presents a grave
problem in that neuropsychological testing by a truly independent
neuropsychologist may be delayed for up to a year before the patient can be
properly tested. The conflicting results may tend to confuse any
trial judge in
a legal case.

G: Depression, Anti-depressive Medications and Myalgic

Myalgic Encephalomyelitis is not depression. Myalgic Encephalomyelitis is
not hysteria. Myalgic Encephalomyelitis is not a conversion disorder nor is it
a somatization disorder. Myalgic Encephalomyelitis is an acute onset
diffuse injury of the brain. Psychiatrists should not ever be placed in charge
of diagnosis and treatment of M.E. patients. It is simply not their area of
expertise and their meddling has at times caused great harm to M.E.
patients. Also, during the 20 years that I have investigated M.E. patients I
have yet to see a single case of real M.E. that has responded to psychiatric
pharmacological treatment such that the patient has recovered and been
able to return to work or school.

This topic is a very large subject and demands a separate publication and
this is not the place for it. However I would like to note again the vascular
and cardiac pathologies that one encounters in M.E. patients and how M.E.
patients are often made worse by one antidepressive medication that is
considered benign. One of the most common antidepressive medications
employed by psychiatrists and physicians in general for M.E. patients is an
old pharmaceutical, Amitriptyline. Yet this medication may result in a
condition referred to as Torsade de Pointes, a cardiac irregularity giving
rise to resting tachycardia, QT interval prolongation and significant
orthostatic hypotension. Since there is already a high frequency of these
anomalies in M.E. patients, the use of Amitriptyline may assist sleep to
some degree but may also simply worsen existing M.E. symptomology. I
plan to return to this subject in another publication.

Definition Changes and Improvements

As with all definitions, the Nightingale Research Foundation's Definition of
Myalgic Encephalomyelitis will have to be looked at by many clinicians and
researchers and over the years, disagreed about, changed and improved
upon. But what this definition does today is (a) separate clearly M.E. from
CFS and (b) demonstrate that M.E. is an early diagnosable and provable
disease - as are all true diseases, and (c) assist in the early treatment and
cure of M.E. patients.

This Nightingale Research Foundation's Definition will be available with any
updates or corrections, on the Nightingale Research Foundation's Website,
http://www.nightingale.ca This definition may be copied, translated,
distributed by electronic or hard copy and may be included, in whole or in
part in any publication without permission from the Nightingale Research
Foundation or the authors, provided that this last paragraph and referral
back to our website are noted.

Byron Marshall Hyde MD, Ottawa - November 18, 2006

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Outgoing mail scanned by Norton AV

From:  Jill McLaughlin <jillmclaughlin@xxxxx.xxx>

IACFS conference - Travel and lodging information

The first block of discounted rooms reserved for conference
attendees at the Bahia Mar Beach Resort has sold out and there
are a very limited number of rooms remaining. There are 4
alternate hotels posted on the website, one which is right next
door at $169, and has a breakfast included.

Information is posted at:

Jill McLaughlin
Membership Committee

*The Conference is January 10-14, 2007. More information and
registration forms are available at: http://www.aacfs.org/


2007 Conference Information » 2007 Patient Conference »
Lodging & Travel » Lodging & Travel

Alternate Hotels listed below
Conference Hotel

Room availability is limited.

Set your bearings for Bahia Mar Beach Resort & Yachting
Center, where magnificent surroundings and legendary service
await you. As the premier choice of Fort Lauderdale hotels this
time-honored destination offers 44 breathtaking acres along the
Intracoastal Waterway. Walk the docks of our acclaimed ocean
front marina, home to many of the world's finest luxury yachts.
Stroll across our skywalk to the vast beach, where the city's heart
beats. Soak up the sunshine on our pristine shores, and enjoy
countless water sports - ranging from sailing and sport fishing to
jet skiing and diving. Journey into town to explore the city's
world-renowned shops, restaurants, art galleries, and nightlife.
Experience the signature essence of the "Venice of America"
from our exclusive oceanfront setting.

Bahia Mar Beach Resort
801 Seabreeze Blvd.
Ft. Lauderdale, FL 33316

Reservations: 888-802-2442 or 954-764-2233 - ask for IACFS
discounted room rate.  The initial room block at the rate of $169
per night is sold out.  We have obtained additional rooms at the
rate of $199.

Alternate Hotels

2 1 2 blocks (walking distance)
Best Western Oceanside
1180 Seabreeze Blvd.
Fort Lauderdale, FL 33316
Rate: $169.00 (SINGLE/DOUBLE), $179.00 (TRIPLE), $189.00
Rates are good until 12/18/06
* Includes full hot breakfast daily
Reservations: All guest should call the hotel directly at
954-525-8115 or 800-367-1007 and ask for reservations :


2 1 2 blocks (walking distance)
Sheraton Yankee Clipper Beach Resort
1140 Seabreeze Blvd.
Fort Lauderdale, FL 33316
Rate: $259
Note: This is their seasonal rate
Reservations: Call 954-524-5551

1.9 miles
Holiday Inn Express
1500 SE 17th Causeway
Fort Lauderdale, FL 33316
Rate $199
Rates are good until 12/18/06
* Includes shuttle to and from the Ft. Lauderdale Airport
* Includes continental breakfast daily
Reservations: Call 954-728-2577 and ask for the IACFS group

4.5 miles
Holiday Inn Express Hotel & Suites
1150 W. State Rd. 84
Fort Lauderdale, FL 33316
Rate $169 king /queen , $189 suite
Rates are good until 12/18/06
* Includes shuttle to and from the Ft. Lauderdale Airport
* Includes continental breakfast daily
Reservations: book online at www.hiexpress.com/air-seaport
enter IAC for the group code or call 954-316-1150 and mention
IAC as the code.


Air Travel

Official Conference Airline- American Airlines

5% Discount provided to IACFS Conference Attendees

Book online at www.aa.com Phone: 800-433-1790

Authorization Code:A0517AA

* certain restrictions apply

Travel discount applies to either Fort Lauderdale International
Airport, approximately 2 1/2 miles from the Bahia Mar Beach
Resort or Miami International Airport, approximately 25 miles
from the Bahia Mar Beach Resort.

Ground Travel Options

Car Rental:
AVIS has agreed to provide discounts to IACFS Conference

Please call 800-331-1600 to receive the best rates.

AVIS Worldwide Discount Number is J991135

Discount is available from either Fort Lauderdale International
Airport or Miami International Airport

Taxi Service

 From Fort Lauderdale International Airport approximately $20

 From Miami International Airport approximately $60

Copyright IACFS, 2004 All Rights Reserved
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Date:    Fri, 1 Dec 2006 17:40:47 -0500
From:    "Bernice A. Melsky" <bernicemelsky@xxxxx.xxx>
Subject: RES: A randomized, sham-controlled, proof of principle study  of transcranial direct current stimulation for the treatment of pain  in fibromyalgia

A randomized, sham-controlled, proof of principle study of transcranial
direct current stimulation for the treatment of pain in fibromyalgia.

Arthritis Rheum. 2006 Nov 28;54(12):3988-3998 [Epub ahead of print]

Fregni F, Gimenes R, Valle AC, Ferreira MJ, Rocha RR, Natalle L, Bravo R,
Rigonatti SP, Freedman SD, Nitsche MA, Pascual-Leone A, Boggio PS.

Harvard Medical School, Boston, Massachusetts.

PMID: 17133529

OBJECTIVE: Recent evidence suggests that fibromyalgia is a disorder
characterized by dysfunctional brain activity. Because transcranial direct
current stimulation (tDCS) can modulate brain activity noninvasively and
can decrease pain in patients with refractory central pain, we hypothesized
that tDCS treatment would result in pain relief in patients with fibromyalgia.

METHODS: Thirty-two patients were randomized to receive sham stimulation or
real tDCS with the anode centered over the primary motor cortex (M1) or the
dorsolateral prefrontal cortex (DLPFC) (2 mA for 20 minutes on 5
consecutive days). A blinded evaluator rated the patient's pain, using the
visual analog scale for pain, the clinician's global impression, the
patient's global assessment, and the number of tender points. Other
symptoms of fibromyalgia were evaluated using the Fibromyalgia Impact
Questionnaire and the Short Form 36 Health Survey. Safety was assessed with
a battery of neuropsychological tests. To assess potential confounders, we
measured mood and anxiety changes throughout the trial.

RESULTS: Anodal tDCS of the primary motor cortex induced significantly
greater pain improvement compared with sham stimulation and stimulation of
the DLPFC (P < 0.0001). Although this effect decreased after treatment
ended, it was still significant after 3 weeks of followup (P = 0.004). A
small positive impact on quality of life was observed among patients who
received anodal M1 stimulation. This treatment was associated with a few
mild adverse events, but the frequency of these events in the
active-treatment groups was similar to that in the sham group. Cognitive
changes were similar in all 3 treatment groups.

CONCLUSION: Our findings provide initial evidence of a beneficial effect of
tDCS in fibromyalgia, thus encouraging further trials.

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Date:    Sat, 2 Dec 2006 12:02:17 +0100
From:    "Dr. Marc-Alexander Fluks" <fluks@xxx.xx>
Subject: RES,NOT: CFS review paper

Soure: Journal of Clinical Virology
       Volume 37, Issue 3, Pages 139-150
Date:  November 2006
URL:   http://www.sciencedirect.com/science/journal/13866532


Chronic fatigue syndrome
L.D. Devanur, J.R. Kerr(*)
Chronic Fatigue Syndrome (CFS) Group, Department of Cellular & Molecular
  Medicine, St. George's University of London, Cranmer Terrace, London SW17
  0RE, United Kingdom
* Corresponding author. Tel.: +44 208 725 5276; fax: +44 208 725 5260.
  E-mail address: jkerr@sgul.ac.uk (J.R. Kerr).

Received 24 July 2006; accepted 18 August 2006


Chronic fatigue syndrome (CFS) is thought to have a worldwide prevalence of
0.4-1% with approximately 240,000 patients in the UK. Diagnosis is based on
clinical criteria and critically depends on exclusion of other physical and
psychiatric diseases. Studies of pathogenesis have revealed immune system
abnormalities and chronic immune activation, dysfunction of the hypothalamic-
pituitary-adrenal (HPA) axis, brain abnormalities, evidence of emotional
stress (comprising host aspects) and evidence of exogenous insults, for
example, various microbial infections (Epstein-Barr virus, enteroviruses,
parvovirus B19, Coxiella burnetii and Chlamydia pneumoniae), vaccinations
and exposure to organophosphate chemicals and other toxins (comprising
environmental aspects). Emotional stress appears to be very important as it
reduces the ability of the immune system to clear infections, it's presence
has been shown to determine whether or not an individual develops symptoms
upon virus infection, and it leads to activation of the HPA axis. But,
emotional stress is distinct from depression, the presence of which
precludes a diagnosis of CFS. There is no specific treatment for CFS other
than the much underutilised approach of specific treatment of virus
infections. Current priorities are to understand the molecular pathogenesis
of disease in terms of human and virus gene expression, to develop a
diagnostic test based on protein biomarkers, and to develop specific
curative treatments.

Keywords: Chronic fatigue syndrome; Virus; Infection; Diagnosis; Pathogenesis;
Gene expression

1. Introduction

Chronic fatigue syndrome (CFS) is characterised by a severe debilitating
fatigue lasting for at least 6 consecutive months. As well as fatigue,
sufferers report numerous other muscular, infectious and neuropsychiatric
symptoms as well as sleep disturbances. CFS is thought to have a worldwide
prevalence of 0.4-1%, with approximately 240,000 patients in the UK and
800,000 patients in the US (Report, 2002; Papanicolaou et al., 2004). CFS
primarily affects women, with a female to male ratio of 6:1. Some studies
also suggest that it is more prevalent in the Caucasian population, however,
this finding could be as a result of greater access to healthcare in this
group rather than an actual increased incidence of CFS in this population

2. Diagnosis

The diagnosis of CFS is currently based on clinical criteria. Various case
definitions for the diagnosis of CFS exist, however the revised definition of
the Centers for Disease Control (CDC) (Fukuda et al., 1994) remains the most
widely accepted, particularly for research purposes. CFS is defined by,
first, clinically evaluated, unexplained persistent, or relapsing chronic
fatigue of new or definite onset (not life-long); not the result of ongoing
exertion; not substantially alleviated by rest; resulting in substantial
reduction in previous activities. Second, the concurrent presence of four or
more of the following symptoms, all of which must have persisted or recurred
during 6 or more months of illness and must not have predated the fatigue;
self-reported impairment in short term memory or concentration severe enough
to cause substantial reduction in previous levels of occupational,
educational, social or personal activities; sore throat; tender cervical or
axillary lymph nodes; muscle pain, multijoint pain without joint swelling or
redness; headaches of a new type, pattern or severity; unrefreshing sleep;
postexertional malaise lasting >24 h. It is also critical to exclude physical
and psychiatric diseases which may cause fatigue. Further characterization of
associated symptoms has also been recommended recently (Reeves et al., 2003).

Currently, there is no laboratory test for CFS, however, this is a priority.
Putative protein biomarkers of CFS have been identified using
surface-enhanced laser-desorption and ionisation time-of-flight (SELDI-TOF)
mass spectrometry (Kerr et al., in press), and if proven to be sensitive and
specific indicators of CFS, their discovery may lead to development of a
diagnostic test for CFS, which would revolutionise our approach to this

3. Pathogenesis

Although the pathogenesis of CFS is incompletely understood, it is likely to
be multifactorial. These factors are best considered in terms of the
arbitrary division into host and environmental factors. However, in practice
within an individual, these two are clearly interlinked with the presence of
particular factors in a particular patient affecting both the likelihood of
development of CFS, and also, probably, its phenotype. However, there is no
evidence to support this last statement, apart from experience with other
diseases, in which, for example, particular gene mutations have been
associated with the presence or absence of certain phenotypic features within
the umbrella of a particular disease itself.

3.1. Host aspects

3.1.1. Immune response

The observation that the onset of CFS is preceded by virus infections and
'flu-like' illness has led researchers to investigate the possible role of
immune dysfunction in the pathogenesis of CFS. Numerous immunological
parameters have been tested and many are abnormal but inconsistently so among
the various studies (reviewed in Natelson et al., 2002). We now recognise
that the immune system plays a crucial role in the pathogenesis of CFS,
however, the precise role played by the immune response remains to be
clarified. A significant increase in the numbers of B cells expressing CD20
and CD21 markers was found in patients with CFS (Klimas et al., 1990). In
contrast, Robertson et al. (2005) have demonstrated that no increase in
either total B cells or CD5+ B cells were present in patients with CFS
compared to healthy controls. An increase in the number of CD8+/HLA-DR+ and
CD8+/CD38+ T cells have been found in patients with CFS, although the trend
was not statistically significant (Robertson et al., 2005). An increase in
this class of T cells has also been observed by Klimas et al. (1990). An
increased state of differentiation of T cells has been observed in patients
with CFS (Straus et al., 1993). However, another study comparing lymphocyte
markers in monozygotic twins has shown that there are no statistically
significant differences between the twins with CFS and the normal twins
(Sabath et al., 2002).

NK cell dysfunction in the pathogenesis of CFS has been widely documented
(reviewed in Whiteside and Friberg, 1998). Tirelli et al. (1994) have shown
that a subset of natural killer cells (NK cells) were increased as were the
total number of circulating B lymphocytes. In contrast, Caligiuri et al.
(1987) have shown a deficiency in NKH.1+ T3 cell numbers and decreased NK
cell function in patients with CFS who had evidence of EBV reactivation.
Klimas et al. (1990) have found a deficiency in cellular immunity in patients
with CFS compared with normals. This deficiency manifested as a decrease in
the cytotoxicity of NK cells, in spite of an increase in total NK cell
numbers. A study measuring NK cell activity in a family with CFS has
demonstrated that although total NK cell populations were not reduced in the
individuals suffering from CFS, there was a decrease in NK cell activity when
compared to healthy controls (Levine et al., 1998). A decrease in NK cell
activity as well as a decrease in antibody dependent cell-mediated
cytotoxicity has also been observed by Aoki et al. (1993). A number of
factors could be responsible for a decrease in NK cell activity, namely, a
shift in NK cell populations leading to an increase in the presence of less
active cells, a decrease in levels of cytokines that modulate NK cell
activity or the presence of an inhibitory factor (Levine et al., 1998).

Various studies suggest that CFS exhibits a Th2 profile of CD4 helper T
lymphocyte responsiveness. Visser et al. (1998) have shown that IFN-gamma
production by CD4 cells from patients with CFS is reduced compared to normal
controls. Skowera et al. (2004a) have shown a significant increase in the
numbers of CD4 and CD8 T cells secreting IL-4 both following polyclonal
stimulation and in resting cell populations from CFS patients compared with
those from controls. An increase in IL-4 production in CFS patients has also
been shown using neural-network classifiers (Hanson et al., 2001). A Th2 type
of immune response has also been proposed (Rook and Zumla, 1997) and observed
(Skowera et al., 2004b) in patients with Gulf war syndrome (GWS), which has a
similar phenotype to CFS. TGF-beta1 mRNA expression appears to be reduced in
patients with CFS (Tomoda et al., 2005). TGF-beta1 is an anti-inflammatory
cytokine and a reduction in the transcription of this protein may increase
the likelihood of inflammation observed in patients with CFS. This is also
consistent with an infectious process.

Neutrophil apoptosis has been found to be increased significantly in CFS
patients as compared with normal controls, lending further support to the
theory of ongoing infection in CFS (Kennedy et al., 2004).

Decreases in levels of circulating IgG subsets have been found in patients
with CFS. Read et al. (1988) have shown a deficiency of IgG1 in two patients
with CFS, with no abnormality in other classes of gamma-globulins. Natelson
et al. (1998) have shown that IgG1 and IgG3 levels are significantly
decreased in patients with CFS as compared with healthy sedentary controls.
It was also found that CFS patients with concurrent axis-I depression had
lower levels of IgG1 and IgG3 compared with patients with CFS alone.
Deficiencies in a number of IgG subclasses have been observed by Komaroff et
al. (1988) in patients with CFS, namely, IgG1, IgG3 and IgG4. A decrease in
IgG3 levels in some patients with CFS has been observed by Linde et al.
(1988). These deficiencies represent a deficiency in anti-viral activity in
patients with CFS, and are likely to contribute to the pathogenesis of

The variability observed when measuring immunological parameters in an
attempt to elucidate the pathogenesis of CFS may arise from a number of
different sources including criteria used for case selection, choice of
controls, differences in study design and methodology, etc. (Pedersen and
Ullum, 1994).

Taken together, these findings suggest that an underlying infection may be
present in these individuals and that the immune system is chronically
activated in response.

3.1.2. Endocrine

The hypothalamic-pituitary-adrenal (HPA) axis functions to maintain
homeostasis during physical and psychological stress. A disruption of the HPA
axis has been implicated in the pathogenesis of CFS (Cleare, 2004). Early
studies have shown that cortisol levels in patients with CFS are reduced
(Poteliakhoff, 1981), where it is suggested that an initial stress results in
a prolonged hyperactivation of the HPA axis, subsequently leading to
insensitivity. It appears unlikely that the decreased levels of cortisol
observed in CFS patients are due to changes to the metabolic pathway
resulting in an increase in the metabolism of cortisol (Jerjes et al., 2006).
One proposed hypothesis (Wheatland and Chronic, 2005) is the formation of
autoantibodies to adrenocorticotropin hormone (ACTH), which is a positive
stimulus for the production and secretion of cortisol by the adrenal glands,
and may lead to a decrease in the production of cortisol. It has been
suggested that a past or persistent infection can lead to the production of
autoantibodies to ACTH.

A link between the immune system and the HPA axis has long been established.
IL-6 has been shown to activate the HPA axis leading to increased plasma ACTH
and corticosterone in studies on mice (Wang and Dunn, 1998). IL-6 and IL-1
have also been shown to synergistically activate the HPA axis and this is
potentiated during emotional stress (Zhou et al., 1996). Conversely, studies
have demonstrated that emotional stress can lead to a rise in blood IL-6
levels, thereby resulting in activation of the HPA axis (Zhou et al., 1993).

It is likely that HPA axis dysfunction is not the cause of CFS, but that it
is secondary to the primary pathogenesis. However, once invoked, HPA axis
dysfunction may act to contribute towards the perpetuation of the illness
(Cleare, 2004).

3.1.3. Brain

Both structural and functional abnormalities have been reported in the brains
of patients suffering from CFS. Much interest has focused on altered
structure and function of cells in the brain as the cause of fatigue in CFS.
The presence of altered cognitive function in patients with CFS has led
researchers to investigate the possible role of disorders of the brain in the
pathophysiology of CFS. Conflicting evidence exists regarding the involvement
of brain abnormalities in CFS. Lesions in the white matter of the brain were
found significantly more frequently in CFS patients without depression than
in CFS patients with depression (Lange et al., 1999), suggesting that CFS
should be divided into subgroups depending on the symptoms. Differences in
brain perfusion between CFS patients and depressive patients has been
observed (MacHale et al., 2000) suggesting a different mechanism in each
case. A study comparing regional cerebral blood flow in monozygotic twins
(Lewis et al., 2001), however, has found no significant difference in
cerebral blood flow between CFS patients and controls. A decrease in absolute
cortical blood flow in patients with CFS has been reported (Yoshiuchi et al.,
2006). A decline in gray matter volume proportional to a decline in physical
activity in CFS has also been reported (de Lange et al., 2005).

Brain positron emission tomography (PET) studies have confirmed the presence
of diminished glucose metabolism in the right mediofrontal cortex as well as
significant hypometabolism in the brain stem of CFS patients (Tirelli et al.,
1998). These authors speculated that certain herpes viruses, for example, EBV
and HHV-6 can accumulate in the brain stem triggering hypometabolism of

A recent study has also demonstrated a decrease in the number and/or affinity
of serotonin receptors in the brain of CFS patients without depression
(Cleare et al., 2005). This would lead to an increase in the free serotonin
levels in the brain, which has previously been reported to result in fatigue
(Blomstrand et al., 1988). Significant reduction in the density of serotonin
transporters in the anterior cingulate gyrus of patients with CFS has been
observed using PET analysis (Yamamoto et al., 2004). A decrease in
N-acetylaspartate (NAA), a marker for neuronal function has been observed
using MR analysis of the hippocampal region of CFS patients compared to
controls, however no decrease in hippocampal volume was noted (Brooks et al.,
2000). Corticospinal activity has been measured by electromyography in
patients with CFS and compared to normal controls; no differences were
observed, although simple reaction times were slower in the CFS group (Zaman
et al., 2001). A study monitoring brain activity in CFS patients and controls
during the performance of simple cognitive tasks has been carried out using
functional MRI (de Lange et al., 2004), showing recruitment of additional
cerebral regions involved in visual processes in CFS patients.

Researchers have put forward a proposal suggesting that increased blood brain
barrier permeability (BBBP) may be involved in the pathogenesis of CFS
(Bested et al., 2001). They suggest that viral replication in cerebral
endothelial cells can increase BBBP through the action of cytokines. In
support of this hypothesis, an increase in choline containing compounds has
been found in the basal ganglia of patients with CFS (Chaudhuri et al., 2003)
and in the occipital cortex (Puri et al., 2002). An increase in these
compounds suggests an increase in cell membrane turnover, which could arise
from viral interaction with host cell membranes. The increase in choline is
also indicative of an abnormality in fatty acid metabolism, which could also
be triggered by a infectious pathogen. Oral supplementation with
eicosapentaenoic acid (EPA) has been found to be beneficial in CFS patients,
with two studies demonstrating the improvement in fatigue (Puri et al., 2004;
Puri, 2004), which is consistent with the anti-viral and immunomodulatory
effects of EPA.

3.1.4. Emotional stress

It is known that emotional stress plays an important role in the pathogenesis
of CFS. The influence of this is complex and is likely the combined result of
an effect on immune responsiveness, the ability of the immune system to
control endogenous virus infection, the ability of the immune system to
effectively handle and clear new virus infections and an effect on the HPA
axis (Glaser and Kiecolt-Glaser, 1998). Emotional stress results in various
changes to the immune system. This has been studied extensively in medical
students and includes decrease in NK cell activity, decrease in
interferon-gamma production by lymphocytes, decrease in cells expressing IL-2
receptor and IL-2R mRNA, decrease in proliferative responses of peripheral
blood lymphocytes to mitogens, decrease in T cell proliferation to EBV
polypeptides (memory response), decrease in T cell killing of EBV transformed
autoloous B lymphocytes (memory response) and evidence of reactivation of
latent herpes viruses (EBV and HSV-1) (Kiecolt-Glaser et al., 1984, 1986;
Glaser et al., 1985, 1986, 1987, 1990, 1992, 1993; Glaser and Kiecolt-Glaser,
1985; Tomei et al., 1990). In addition, stress is known to have a significant
modulating effect on the pathogen- esis of virus infection. Cohen et al.
(1991) reported that in human volunteers inoculated with five respiratory
virus strains, there was a dose­response curve between amount of stress and
development of clinical symptoms and their severity.

The principal means by which this influence occurs is likely to be via the
HPA axis. It is known that emotional stress can upregulate the expression of
corticotropin-releasing hormone (CRH) through the hypothalamus, which
stimulates production and release of adrenocorticotrophic hormone, which in
turn result in release of hydrocortisone which then downregulates immune
responses. These hormones have been shown to enhance lytic infection with EBV
in vitro (Glaser and Kiecolt-Glaser, 1998).

Therefore, emotional stress is known to influence immune responsiveness and
virus pathogenesis, and has profound importance to our understanding of the
pathogenesis of infectious diseases and cancer, and may therefore be a key
aspect in the pathogenesis of CFS.

However, it must be emphasized that emotional stress is not the same as
depression, which is an exclusion criterion for a diagnosis of CFS.

3.2. Environmental aspects

3.2.1. Infection

The fact that many cases of CFS begin with a flu-like illness alerted
clinicians and researchers to the possibility that this illness could be
triggered by infection. This has subsequently been shown to be the case using
various approaches. First, it has been possible to confirm the presence of
infection in patients with CFS patients who present to the clinic many months
after the onset of their illnesses (Chia and Chia, 2003). Second, outbreaks
of CFS have been documented which have been shown by laboratory investigation
to be caused by outbreaks of particular infectious agents, for example, with
C. burnetii and enteroviruses (Ayres et al., 2002; Chia, 2005). Third, when a
cohort of patients suffering from acute infection with a particular
infectious agent are followed in time, a subset of these have been shown to
develop CFS with an onset contemporaneous with the onset of the particular
microbial infection. For example, parvovirus B19 and Epstein-Barr virus (Kerr
et al., 2001, 2002; White et al., 2001).

Numerous studies have investigated the role of infections in the pathogenesis
of CFS and various viruses and virus groups have been implicated in CFS at
some time; these include Epstein-Barr virus (EBV), cytomegalovirus,
parvovirus B19, Brucellae, Toxoplasma gondii, C. burnetii, C. pneumoniae,
human herpes virus-6 (HHV-6), group B coxsackieviruses (CVB), human T cell
leukaemia virus II-like virus, spumavirus, hepatitis C virus, human
lentiviruses and herpes virus-7. These are summarised in Table 1, and some
important aspects and opportunities for management of such cases are
discussed below.

It is likely that virus infection plays a role in a majority of cases of CFS.
As with other diseases, early beliefs that CFS may be triggered or caused by
a single virus have been shown to be unsubstantiated. Instead, it is clear
that various different microbial infections can trigger the disease, and it
is likely that different viruses affect different individuals differently,
dependent on the host genetic make-up and the immune competence of the
individual, which is dependent on various factors including
immunosuppression, emotional stress, previous infections, etc. It appears
that viruses may trigger CFS by either a hit-and-run mechanism (in which the
virus is present at the beginning of the illness but cannot be detected later
in the illness) or through a persistent infection (in which the virus is
present both at the beginning of the illness and and after months or years
and is detectable in patients with CFS presenting to the clinic).

3.3. Infections triggering CFS for which an established treatment exists

Currently, we do not understand the precise pathogenesis of CFS and there is
therefore no specific treatment available for CFS patients. However,
infections are known to trigger and perpetuate the disease in many cases.
Therefore, one potentially valuable approach which has not yet been widely
adopted in the management of CFS patients is to exhaustively investigate such
patients in the hope of identifying evidence for a specific persistent
infection. If such evidence is found, then a trial of the relevant
anti-microbial drug(s) may then be warranted. There are many infectious
agents which are known to trigger and perpetuate CFS, and which have been or
may be targetted with anti-microbial therapy. In some of these instances,
there has been clear evidence of clinical benefit or cure in infected CFS
patients. Some of these infections are discussed in more detail below.

3.3.1. Enteroviruses

Enteroviruses are well known causes of acute respiratory and gastrointestinal
infections, with tropism for the central nervous system, muscles and heart.
Enteroviruses have been reported to trigger approximately 20% of cases of CFS
(Yousef et al., 1988; Gow et al., 1991). Antibodies to coxsackie B virus are
frequently detected in CFS patients, and enterovirus protein and RNA occur in
the muscle and blood of CFS patients (Yousef et al., 1988; Gow et al., 1991;
Clements et al., 1995), and their presence has been associated with altered
metabolism in the muscle upon exercise in the context of CFS (Lane et al.,
2003). Viral persistence through the formation of stable double stranded RNA
may explain the apparent discrepancy between an absence of live virion in
chronically infected patients and animals along with the presence of
enteroviral RNA in the blood or other tissues (Chia, 2005). In addition,
interferon-alpha and interferon-gamma act synergistically against enterovirus
in vitro, and preliminary studies suggest that this combination may be an
effective treatment for patients with chronic enteroviral infection (Chia,

3.3.2. Parvovirus B19

Human parvovirus B19 is the cause of aplastic crisis in patients with
shortened red blood cell survival, erythema infectiosum, arthritis, fetal
death and persistent infection in immunocompromised individuals (Kerr and
Modrow, 2006). B19 virus infection has been shown to lead to development of
CFS (Jacobson et al., 1997; Kerr et al., 1996, 2002). B19-associated CFS
developed in 4­13% symptomatically infected persons (Kerr et al., 1996,
2002). In these patients, elevated circulating levels of tumour necrosis
factor- (TNF-alpha) and interferon-gamma (IFN-gamma) were reported and are
consistent with the chronic immune activation characteristic of CFS patients
(Kerr et al., 2001). Most of these patients exhibited circulating B19 DNA at
the time of presentation (Kerr et al., 2002) and three were cured by
administration of the only specific treatment for B19 infection, namely,
intravenous immunoglobulin (IVIG), which also coincided with complete
normalisation of cytokine dysregulation (Kerr et al., 2003).

3.3.3. Epstein-Barr virus

EBV is a ubiquitous human virus that is transmitted in saliva. EBV infection
in normal individuals causes infectious mononucleosis and a percentage of
these go on to develop CFS (Jones, 1988; Straus et al., 1985). Early reports
that differences in EBV-specific antibody responses occur in those
EBV-infected individuals that develop CFS as compared with those that do not,
have been shown to be unsubstantiated (Buchwald et al., 1987). A recent study
reports that in 10 CFS patients with persistent EBV infection, use of
valacyclovir for 6 months led to a significant clinical benefit (Lerner et
al., 2002).

3.3.4. C. pneumoniae

C. pneumoniae is a human pathogen which is transmitted by aerosol droplets
and causes community-acquired pneumoniae and various other clinical
manifestations. C. pneumoniae has been shown to cause CFS (Nicolson et al.,
2003; Chia and Chia, 1999, 2003) and patients with CFS with a high prevalence
of C. pneumoniae persistent infection were shown to respond clinically to
treatment with azithromycin (Chia and Chia, 1999).

3.3.5. C. burnetii

C. burnetii is a zoonotic infection which may result in a wide variety of
clinical manifestations, including influenzalike illness, pneumonitis,
hepatitis, endocarditis and CFS. It is amenable to treatment with a variety
of agents. Arashima et al. (2004) observed an improvement in fatigue in
patients sero-positive for C. burnettii infection following minocycline
treatment, although this benefit does not appear to be universal (Iwakami et
al., 2005). Toxin exposure.

The role of environmental toxin exposure in the development of CFS has been
identified and evidence exists for the role of toxins in the development of
symptoms of fatigue. Studies have been conducted to monitor the levels of
toxins in the blood of patients with CFS with a view to determine whether
they have any influence of the pathogenesis of disease. Dunstan et al. (1995)
have shown that the levels of organophosphates in the blood of CFS patients
were higher than in control subjects and comparable to that of CFS patients
with known chemical exposure. It has been shown that ciguatera fish toxin
poisoning can lead to CFS and that immunological and HPA axis abnormalities
are observed in these patients at higher frequency than patients suffering
from CFS following EBV infection (Racciatti et al., 2001). Although acute
symptoms of ciguatera poisoning last approximately 1 week, the neurological
symptoms may be present for months or even years. The neuropsychological
performance of farmers exposed to organophosphates was found to be
significantly lower than people not exposed to this toxin (Tahmaz et al.,
2003). Stephens et al. (1996) have also demonstrated that exposure to OPs can
cause nervous system abnormalities.

Many symptomatic parallels can be drawn between Gulf war syndrome and CFS
(Fiedler et al., 1996). GWS is thought to arise from exposure to numerous
chemicals. The development of GWS in some, but not all Gulf war veterans,
highlights the possibility that genetic predisposing factors are crucial for
the development of GWS. Butyrylcholinesterase (BChE) and paraoxonase/
arylesterase (PON1) are involved in the binding/sequestration and hydrolysis,
respectively, of organophosphates (OPs). Prolonged exposure to OPs is known
to inactivate BChE and therefore PON1 remains the only mechanism for
detoxification of these poisons. Haley et al. (1999) have demonstrated that
a particular mutation in the PON1 gene is highly correlated with development
of GWS in Gulf war veterans, and it is possible that patients suffering from
CFS also carry this mutation. Mackness et al. (1997) have demonstrated that
PON1 mutations do lead to a diminished rate of hydrolysis of paraoxon. The
role of pesticides in the development of neuropsychiatric conditions has
been widely documented (reviewed in Kamel and Hoppin, 2004) and it has been
shown that exposure may lead to CFS/GWS.

A link between exposure to mould and neuropsychiatric symptoms has been
established (Crago et al., 2003). Vaccination.

Immunisation of humans with vaccines of many types commonly results in a
flu-like illness in which fatigue is routinely present. In addition,
immunisation with various vaccines have been reported to trigger CFS. These
vaccines include MMR, pneumovax, influenza, hepatitis B, tetanus, typhoid and
poliovirus (Lloyd et al., 1988; Symmons et al., 1993; Gross et al., 1995;
Grotto et al., 1998; Hyde, 1999; Report, 1993; Vedhara et al., 1997; Chia and
Chia, 2003).

The relationship between vaccination and development of fatiguing illness is
much better established in the case of GWS, probably because in GWS multiple
vaccines were used as part of intensive immunisation schedules. Both Unwin et
al. (1999) and Hotopf et al. (2000) have demonstrated a correlation between
multiple immunizations during deployment of service personnel to the Gulf and
the presence of subsequent ill-health. It has been found that Gulf war
veterans who received anthrax vaccination were more likely to develop
symptoms similar to CFS when compared to veterans who did not receive anthrax
vaccination (Schumm et al., 2002). Pertussis, which is used as an adjuvant in
anthrax vaccines in the UK is thought to cause a systemic shift in the immune
response towards a Th2 profile (Rook and Zumla, 1997), characteristic of CFS
and GWS (Skowera et al., 2004a,b). Pyridostimine is used as an anti-nerve gas
agent in Gulf war personnel. It has been demonstrated that the combination of
pyridostimine and vaccinations can lead to activation of stress-induced
kinases in the brains of mice (Wang et al., 2005). Stress at the time of
deployment is also certain to be a contributing factor.

4. Treatment

As we do not understand the pathogenesis of CFS, it is impossible to make
specific therapeutic interventions. The one exception to this is in the area
of infection. For example, if a particular infection can be identified, then
the specific therapy can be used, and this is often beneficial.

4.1. Specific therapies

The fact that CFS is frequently triggered and perpetuated by ongoing
microbial infection has led to the proposed approach of exhaustive
investigation to find an infectious cause of a patient's symptoms, which may
then indicate a specific anti-microbial drug regimen that can be used to
eradicate that infection with resultant clinical benefit (Chia and Chia,
2003). There are sufficient infections whose association with CFS is
prominent to make this approach a useful one in terms of potential benefit to
a large number of CFS patients. For example, Epstein-Barr virus,
enteroviruses, parvovirus B19, C. pneumoniae and C. burnetii (see above).
This approach is standard in the management of patients with pyrexia of
unknown origin (PUO), often with good results. So, why is it such a barrier
for us to apply these simple and universally accepted practices to a disease
in which infection frequently plays a major role? Along similar lines,
immunestimulant therapy through weekly injections of staphylococcus toxoid
led to marked improvements in the symptoms of patients with CFS suggesting
that immune activation was key in the clearance of pathogens (Zachrisson et
al., 2002).

Hydrocortisone has been used to correct abnormalities in the HPA axis (Cleare,
2003); this has been shown to lead to a significant improvement in symptoms
of disease in CFS patients and a reduction of dehydroepiandrostenedione (DHEA)
to normal levels, but may also be complicated by adrenal suppression (McKenzie
et al., 1998).

4.2. Non-specific therapies

The use of anti-depressants, NSAIDs, anxiolytic drugs, stimulants,
anti-allergy drugs and anti-hypotensive drugs have all been reported, but are
not universally beneficial (Afari and Buchwald, 2003). Recently, the use of
methylphenidate, an amphetamine-derived stimulatory drug, has been shown to
significantly improve fatigue and concentration disturbances in people
suffering from CFS (Blockmans et al., 2006). Randomised controlled trials
have been carried out to determine the effectiveness of intravenous Ig
therapy in the treatment of CFS with conflicting results. Two such studies
have reported no beneficial effect of IgG therapy on the symptoms of CFS
(Vollmer-Conna et al., 1997; Peterson et al., 1990), however one study has
demonstrated a beneficial effect of Ig therapy (Lloyd et al., 1990). IVIG
therapy is recognized to benefit individual CFS patients although it is
difficult to predict which patients may benefit.

The failure of conventional therapies to provide adequate relief from the
symptoms of CFS has led sufferers to experiment with various alternative
therapies with markedly differing outcomes (Tharakan and Manyam, 2006; Gregg,
1997; Sekiya et al., 2005; Mears, 2005; Sackner et al., 2004;
Weatherley-Jones et al., 2004; Ernst, 2004).

The TNF-alpha inhibitors may provide benefit in CFS. This group of drugs has
been shown to lead to dramatic improvement in patients with rheumatoid
arthritis, Crohn's disease, psoriasis and other diseases including asthma.
One TNF-alpha inhibitor (etanercept) has been used with significant benefit
in the treatment of 6 CFS patients in a pilot study (Lamprecht et al., 2001).
Unfortunately, this trial was not published as a paper, but only as a meeting
abstract. This requires urgent confirmation in a larger subset of patients.

4.2.1. Psychological therapies

Graded exercise therapy (GET) and cognitive behavioural therapy (CBT) remain
the most common methods of treatment for CFS available on the NHS. The
rationale for GET is that increasing amount of exercise will 'blow out the
cob- webs' and return the patient to a normal or near-normal level of
activity. The rationale behind CBT is that patients are encouraged to gain
insights into the effects that particular activities have on their physical
functioning, and thereby to gain an increased ability to tailor their
activities to their capabilities. Numerous studies have been conducted to
determine the effect of graded exercise therapy on patients with CFS despite
the fact that it is known to have a detrimental effect on many patients.
While some studies report benefit of CBT, this is admitted by it's proponents
to be a minor benefit and not a cure. In addition, a significant proportion
of patients show no improvement following CBT (Akagi et al., 2001; Huibers et
al., 2004). Neither GET nor CBT are specific treatments for CFS, as we do not
yet understand the pathogenesis of CFS.

Preventing serotonin uptake has been found to be beneficial in CFS patients
with secondary depression. A pilot study investigating the possible
beneficial effects of the use of the serotonin receptor antagonists,
tropisetron and ondansetron on fatigue in patients with CFS showed
improvement in fatigue but not any other symptoms (Spath et al., 2000). The
use of a serotonin receptor antagonist, granisetron, has shown promising
results with regard to fatigue levels, albeit in a pilot study with no
placebo (The et al., 2003). The use of the serotonin receptor antagonist,
nefazodone, has shown improvements in symptoms of pain and insomnia in all
three patients and two of the three patients also showed improvements in NK
cell function (Goodnick and Jorge, 1999).

4.3. Supplements to support normal physiology

The use of vitamin and mineral supplementation is very common in those
suffering from CFS and is in our view advisable if high quality preparations
are used. In addition, use of anti-oxidants in these preparations is of clear
benefit due to their role in reducing inflammation and the toxic effects of
superoxide radicals and excessive oxidation, which is recognised as a problem
in CFS (Kennedy et al., 2005). For example, a 2-month trial with l-carnitine
has shown improvements in fatigue in patients with CFS (Plioplys and
Plioplys, 1997). The use of l-glutamine is also advisable to aid in repair of
the gastrointestinal tract (GIT) and to reduce the catabolic effects on
muscles of a debilitating illness. It is known that a deficiency in essential
fatty acids may lead to impairment of the immune response due to a decrease
in production of cytokines. In this regard, oral supplementation with
eicosapentaenoic acid has been found to be beneficial in CFS patients, with
two studies demonstrating the improvement in fatigue (Puri et al., 2004;
Puri, 2004), which is consistent with the anti-viral and immunomodulatory
effects of EPA.

5. Current priorities in CFS

There are currently three priorities in the area of CFS research; to
understand the pathogenesis, to develop a diagnostic test and to obtain
effective treatments.

5.1. Understanding the pathogenesis

Information generated by sequencing of the human genome along with advances
in manufacture of automated chips and data analysis has provided the
potential to correlate the genome of an organism with its biological
functions. Analysis of gene expression in peripheral blood white blood cells
has become a standard methodological approach to study of the pathogenesis of
many human diseases and these studies are ongoing in CFS. Considering those
studies of gene expression in CFS in which results have been confirmed using
PCR (Powell et al., 2003; Kaushik et al., 2005; Grans et al., 2005, 2006;
Kerr et al., unpublished), the genes identified in CFS suggest a complex
picture but most prominent within which is 'immunity and defense'. This
supports previous findings on the role of the immune system in the
maintenance of this disease.

But the ultimate goal in all of these studies has not yet been achieved;
namely to identify with complete certainty those genes whose overexpression
or underexpression occurs in patients with CFS, but not in either normal
persons or in patients with other diseases. In addition, such research must
be comprehensive enough to identify particular metabolic pathways that are
involved in CFS. Therefore, we must use methods that look at all known genes
and then be able to group the genes together so that we have knowledge of the
pathways involved. This work is ongoing in our Department (Kerr et al., in
press) and in several other laboratories. Once we have a clear picture of the
metabolic pathways which are abnormally activated or deactivated in CFS, we
can then consider options for molecular intervention in order to correct the
abnormalities and, hopefully, restore normal function.

5.2. Development of a diagnostic test

Progress is also being made towards identifying biomarkers in the serum of
patients with CFS. A biomarker is a protein that occurs at different levels
in the serum of patients when compared with normal people and patients
suffering from other diseases. This work is being done using SELDI-TOF mass
spectrometry (www.ciphergen.com). In this technique, minute amounts of serum
are spotted onto the surface of aluminium chips which are then subjected to
an ionisation current. This method combines chromatographic separation,
achievable due to the presence of biochemically active chip surfaces, with
mass spectrometry. Based on the time-of-flight, the mass/charge (m/z) ratio
for each molecule is determined. The method is able to determine the mass and
relative amount of each individual molecule in complex protein mixtures.
Analysis of mass spectra from cases as compared with controls, identifies
peaks (or proteins) the presence or absence of which can reliably distinguish
between the two groups. It is these proteins (or combinations of them) which
can then be used as biomarkers in a diagnostic test, assuming they are shown
to be specific to patients with CFS.

The development of such a test, in either ELISA or dipstick format, would
revolutionise the diagnostic process in patients with CFS through simplifying
it and, hopefully, reducing the need for exhaustive exclusion of a long list
of other disease which may also cause fatigue.

5.3. Development of effective treatments

Knowledge of how a disease is caused leads directly to design and utilisation
of treatments which correct the abnormal processes and, hopefully, lead to
improvement or cure of the disease. In the context of genomic research, many
treatments have been designed in this way. For example, a range of so-called
'biologic' treatments are now available for immune-mediated diseases.

On the basis of the results of gene expression studies, and what is known of
the pathogenesis of CFS, a clinical trial of interferon-beta (IFN-beta) is
planned at St. George's University of London. We envisage that this will be
first of several clinical trials that are based on our gene expression
findings, using the novel gene approach outlined elsewhere (Kerr et al., in


We thank the CFS Research Foundation for funding of this work.


Table 1. Virus infections which have been associated with development of CFS
Infectious agent linked    Is persistence  Treatments used for this       References
with CFS                   a feature of    infection in the context
                           this infection  of CFS
Enteroviruses              Yes             Interferons alpha,gamma        Yousef et al. (1988), Gow et al. (1991),
                                                                          Clements et al. (1995), Chia (2005), Chia
                                                                          and Chia (2003), Lane et al. (2003)
Epstein-Barr virus (EBV)   Yes             Valacyclovir                   Jones (1988), Straus et al. (1985), White
                                                                          et al. (2001), Lerner et al. (2002)
Cytomegalovirus (CMV)      Yes             Cidofovir, IVIG                Chia and Chia (2003)
Human herpes virus-6       Yes             Cidofovir                      Ablashi et al. (2000), Chia and Chia
   (HHV-6)                                                                (2003), Nicolson et al. (2003)
Parvovirus B19             Yes             IVIG                           Jacobson et al. (1997), Kerr et al.
                                                                          (2001, 2002, 2003)
Hepatitis C                Yes             Interferon/ribavirin           Chia and Chia (2003)
Chlamydia pneumoniae       Yes             Tetracycline, charithromycin   Chia and Chia (1999, 2003)
Coxiella burnetii          Yes             Tetracyclines                  Arashima et al. (2004)


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