ME/CFS -Evidence Cardiovascular Problems, that NICE disregarded

[Guest guest]

Reasons for Judicial Review of the NICE Guideline

The article below by Margaret , about the

Evidence of Cardiovascular Problems in ME/CFS, is

the third in a series of four; specifically created for

Judicial Review of the NICE Guideline. There is some

duplication of documents already published.

1. *CBT cannot improve ME/CFS* (see Help ME

Circle, 30 October 2008 - original document was

attached to this issue. (private members)

2. *the potential dangers of graded exercise

therapy*; Help ME Circle, 2 November 2008- the

original document was also attached to that issue.

(private members)

3. Below is the third in the series; it's on

cardiovascular issues: *ME/CFS -Evidence

Cardiovascular Problems, that NICE disregarded*

the original document is attached to this issue.

(private members)

To be continued:

4 * Immune / neuro / endocrine issues

All three original files (doc) can also be

downloaded from:

1)

http://rapidshare.com/files/160499897/MargaretW_CBT_cannot_improve_ME_CFS_Backgr\

ound_inf___illustr_of_evidence_which_NICE_disregarded.doc

2)

http://rapidshare.com/files/160141234/MargaretW-ME_CFS___Dangers_of_Graded_Exerc\

ise.doc

3)

http://rapidshare.com/files/161565834/MargaretW-Evidence_of_cardiovascular_probl\

ems_in_ME_CFS.doc

~jvr

````````

Evidence of cardiovascular problems

in ME/CFS that NICE disregarded

Margaret

4th August 2008

Executive Summary

Myalgic Encephalomyelitis / Chronic Fatigue

Syndrome (ME/CFS) is an organic, multi-system

disorder involving major systems and organs,

particularly the neurological system (central and

autonomic), the immunological system, the

endocrine system, the cardiovascular system, the

respiratory system, the muscles, the

gastro-intestinal system, the urological system, the

reproductive system, the auditory system, the ocular

system and the skin, and pain is often a significant

feature. There is abundant published evidence of

multi-system dysfunction in ME/CFS but this

document looks at some of the evidence concerning

just one system that is dysfunctional in ME/CFS: the

cardiovascular system.

Cardiovascular dysfunction in ME/CFS patients has

been well documented for many years. As long ago

as 1957, Dr Wallis recorded " myocarditis,

with dyspnoea on slightest exertion " . Professor

Behan wrote in 1988 that " evidence of cardiac

involvement may be seen " , and Dr Jay Goldstein

noted in 1990 that " a significant group have

cardiac symptoms " . An important study by Professor

Natelson and Dr Arnold Peckerman

published in 2003 demonstrated that there might

be periods in daily activities when demands for

blood flow are not adequately met, compromising

metabolic processes, including the possibility of

under-perfusion in the kidneys and gut.

It may, therefore, be seen as both inexplicable and

inexcusable that the NICE Guideline Development

Group (GDG) who on 22nd August 2007 produced the

NICE Guideline CG53 on " CFS/ME " chose to ignore –

and was directed to disregard - an evidence-base of

over 4,000 published studies showing underlying

biological abnormalities in ME/CFS patients, studies

that include extensive evidence of cardiovascular

problems: the Guideline specifically stipulates that

" signs and symptoms of cardiorespiratory disease

should not be attributed to CFS/ME " and refers

instead to " perceived exertion " .

The Guideline makes no reference to the

fact that people with ME/CFS are not

permitted to be blood-donors.

The GDG also ignored calls for the subgrouping of

ME/CFS patients, with the result that the NICE

Guideline has recommended the national

implementation of a behavioural management regime

(cognitive behavioural therapy and graded exercise

therapy) for all patients with " CFS/ME " , a regime that

may be potentially fatal for an unknown number of

patients.

Where it does refer to subgrouping, the Guideline

seems only to be talking about the difference

between the mildly, or moderately, or severely

affected patients, not to distinct clinical categories.

Of particular note is the fact that in its Comments on

Stakeholder submissions, NICE states that it

advised that " CFS/ME " is a physical disorder; NICE

has not recommended behavioural interventions

as the only intervention for any other physical

disorder for which it has produced a Guideline.

As a result of these failings by NICE, this document

seeks to look in particular at the following key areas:

(i) The need for an accurate case definition

of ME/CFS

* There are now at least eleven different

case definitions of supposedly the same

disorder

* NICE insists that " CFS/ME " is the same

as ME/CFS – but the World Health

Organisation (WHO) does not agree,

classifying ME/CFS as a discrete

neurological disorder (ICD-10 G93.3)

* The most significant obstacle to accurate

diagnosis is the continued failure

(particularly in the UK) to adopt the most

effective case-definition (i.e. the 2003

Canadian case definition).

(ii) The need for subgrouping of " CFS /ME "

* Flaws in the case definition and in the

design of (mostly UK) epidemiological

studies have " led to inaccurate and

biased characterisation of CFS " which

incorrectly favour a psychiatric view of the

disorder

* Subgrouping of " CFS/ME " is important

and necessary and there is extensive

literature supporting the need for it.

* A significant percentage (at least 20%)

of people with ME/CFS as distinct from

" CFS/ME " die from cardiac failure.

(iii) Evidence and illustrations of cardiovascular

dysfunction in ME/CFS that the NICE GDG was

directed to disregard

* " The blood vessels throughout the

nervous system were distended with red

blood cells … the most characteristic

change was infiltration of the blood

vessel walls "

* " ME is a multisystem syndrome including

nervous, cardiovascular, endocrine and

other involvement. Vasculitic skin lesions,

autonomic dysfunction, especially

circulation and thermoregulation "

* " These chronic ME/CFS patients

complain of severe chest pain and

shortness of breath as if suddenly

stopped by an invisible barrier "

* " Evidence of cardiac involvement may be

seen: palpitations, severe tachycardia with

multiple ectopic beats and occasional

dyspnoea may occur and are quite

distressing. It is of great interest that

some patients have evidence of

myocarditis "

* " There is a high incidence of

cardiomyopathy in CFS patients "

* " Convincing evidence of cardiovascular

impairment can be demonstrated "

* " As a group, the ME/CFS patients

demonstrated significantly lower

cardiovascular as well as ventilatory values

compared with the control group. These

results indicate either cardiac or

peripheral insufficiency embedded in the

pathology of ME/CFS "

* " Several groups have shown that ME/CFS

patients have abnormal regulation of heart

rate and blood pressure, as well as high

rates of allergic disease "

* " Many people with ME/CFS may have a

serious heart problem. When you exercise,

your heart pumps out more blood. But

these patients' hearts actually pump less

blood "

* Without exception, every disabled

CFIDS (ie ME/CFS) patient is in heart

failure

* " " Q " stands for cardiac output in litres

per minute. In ME/CFS patients, Q values

correlated – with great precision – with the

level of disability. When disabled ME/CFS

patients stand up, they are on the edge

of organ failure due to extremely low

cardiac output as their Q drops to 3.7

litres per minute (a 50% drop from the

normal of 7 litres per minute)

* " All disabled ME/CFS patients, all of

whom have post-exertional fatigue, have

low Q and are in heart failure "

* In order to improve cardiac output in

ME/CFS, patients need to lie down, as this

increases the cardiac output by 2 litres per

minute. Some ME/CFS patients need to lie

down all the time to augment their blood

volume in order to survive

* Aerobic exercise may kill the patient

with ME/CFS. There is an objective

database in key medical literature that

includes evidence of diastolic dysfunction

and heart failure in ME/CFS

* After 10 years of illness, there is only a

30% chance of any functional recovery

* ME/CFS is a compensatory response to

down-regulate energy production and

oxygen transport in order to reduce tissue

damage. Attempts to push beyond energy

limits will cause injury

* Diastolic failure begins when the body

can no longer compensate and there is a

reduction in cardiac output. This is seen

in 80% of ME/CFS patients

* In order to stay relatively stable, it is

essential for the ME/CFS patient not to

create metabolic demand that the low

cardiac output cannot match

* Graded exercise therapy is ill-advised

– if a patient has abnormal oxygen

consumption, muscles will not have

enough oxygen and exercise will result in

relapse

* The cardiac index of ME/CFS patients

is so severe that it falls between the

value of patients with myocardial

infarction (heart attack) and those in

shock.

(iv) Conclusion

* It is essential to ascertain how, in the

light of so much evidence of serious heart

and vascular problems in a subset of

ME/CFS patients (all of which the GDG was

directed to disregard) incremental aerobic

exercise as recommended in the NICE

Guideline can help such patients remain as

functional as possible

* Evidence should be produced by NICE as

to why such an important Guideline was so

restricted in its remit that it was not

allowed to consider the totality of the

existing evidence-base on ME/CFS

* A credible explanation should be sought

from NICE as to why only those

professionals who support a behavioural

model of " CFS/ME " were selected to be

members of the GDG.

Evidence of cardiovascular problems

in ME/CFS that NICE disregarded

Myalgic Encephalomyelitis / Chronic Fatigue

Syndrome (ME/CFS) is a complex disease affecting all

the major systems and organs of the body, including

the cardiovascular system, where extensive damage

has been identified (M Hooper. J Clin Pathol

2007:60:466-471).

There are over 4,000 peer-reviewed papers

documenting the biomedical underpinnings of

ME/CFS.

However, a group of UK psychiatrists and their

adherents known as the Wessely School (Hansard

[Lords] 19th December 1998:1013) deny and dismiss

this scientific and biomedical evidence and have

spent the last two decades proclaiming their belief

that ME/CFS does not exist as a nosological entity

and that it is " like the elephant to the blind man –

simply (a) different part of the same animal " , the

elephant being a single somatoform (behavioural)

disorder (S Wessely et al. Lancet

1999:354:936-939).

These psychiatrists are advisers to UK Government

agencies and to the medical insurance industry and

they have assiduously published their beliefs; it is

largely their studies that form the basis of the

Systematic Reviews upon which NICE has relied as

its " evidence-base " for its recommended

management regime in its Guideline CG53 on

" CFS/ME " published on 22nd August 2007. Since

virtually all the papers on the management of

" CFS/ME " that were included in the Systematic

Reviews had been written by the Wessely School

psychiatrists and adherents themselves, those

Systematic Reviews support the Wessely School's

view that behavioural interventions are the

management regime of choice.

In the current issue of the British Medical Journal

there is an Editorial by Professor Sir Iain Chalmers

entitled " Confronting therapeutic ignorance. Tackling

uncertainties about the effects of treatments will

help to protect patients " (BMJ 2008:337:a841). Sir

Iain writes:

" This week's BMJ includes the first of a series of

articles on areas of practice where clear and robust

evidence is lacking, and where uncertainty exists

about management.

Our failure to confront uncertainty about the

effects of treatment has resulted in the suffering

and death of patients, sometimes on a massive

scale.

Thousands of systematic reviews have shown that

the existing evidence does not answer important

questions about the effects of many treatments.

More fundamental changes are needed to reduce the

damage being done to patients by failure to confront

uncertainties. Hyper-regulation has made it easier

for clinicians simply to acquiesce in therapeutic

ignorance. The consequences for patients of

acquiescing in therapeutic ignorance can be

disastrous, yet current attitudes are powerful

disincentives to people who wish to confront

uncertainties about the effects of treatments " .

Nowhere is this more apposite than to the national

management regime recommended in the NICE

Guideline CG53 on " CFS/ME " .

Because of the failure to confront management

uncertainty, and in defiance of the well-documented

evidence of contra-indications that were submitted

to it (for which it claimed that it could not find any

evidence), NICE has recommended the national

implementation of a management regime for all

patients with " CFS/ME " that may be potentially

fatal for an unknown number of patients.

The need for an accurate

case definition of ME/CFS

Including its own new case definition for " CFS/ME "

that, without due consultation, was introduced by

NICE itself in its Guideline on " CFS/ME " , there are

now at least eleven different case definitions of

supposedly the same disorder.

Apart from the case definition introduced by NICE

and the widely-acclaimed Canadian Case Definition

(Carruthers B et al. 2003: ISBN 0-7890-227-9, see

below), nine case definitions are listed on page 88 of

The National Task Force Report on Chronic Fatigue

Syndrome/Post Viral Fatigue Syndrome/Myalgic

Encephalomyelitis, 13th September 1994 (produced

by Westcare, now part of Action for ME, and

supported by the Department of Health).

Advised by Wessely School psychiatrists and

adherents, NICE insists that " CFS/ME " is the same as

" ME/CFS " but the World Health Organisation (WHO)

does not agree, classifying ME/CFS as a discrete

neurological disorder (ICD-10 G93.3) and classifying

states of chronic fatigue as behavioural disorders

(ICD-10 F48.0).

The Wessely School, however, does not accept the

WHO classification of ME/CFS: Wessely asserts that:

" Neurasthenia would readily suffice for ME " (Lancet

1993:342:1247-1248), and he subsumes the distinct

disorder ME into the psychosomatic label " CFS/ME "

that he has constructed (BMJ 2003:326:595-597).

It is notable that the Guideline Development Group

(GDG) states on page 36 of the GDG Comments on

Stakeholder submissions on Chapter 2:

" a recommendation that CFS/ME should be

recognised as a physical illness has been made " , but

this is not explicit in the published Guideline and,

significantly, the only management recommendation

is a behavioural modification programme.

NICE has not recommended a behavioural

modification programme as the only intervention

for any other physical disorder for which it has

produced a Guideline.

The GDG further states: " Support for specific

physical features of the syndrome was weak and

inconsistent in the studies reviewed for this

Guideline " . Herein lies the nub of the problem,

because the studies on which NICE has based its

recommended management regime are limited to

those of the Wessely School and ignore an

evidence-base of over 4,000 peer-reviewed published

papers that show the Wessely School to be wrong.

The Canadian Criteria

There is international agreement that the most

significant obstacle to accurate diagnosis is the

continued failure (particularly in the UK) to adopt the

most effective case definition (i.e. the 2003

Carruthers et al Canadian case definition, this being

the one that distinguishes the discrete disorder

ME/CFS from the heterogeneous " CFS/ME " , yet

its use is specifically proscribed by NICE).

The Canadian Guidelines are critical of the UK

trials upon which the GDG relied for its alleged

evidence-base (Myalgic Encephalomyelitis/Chronic

Fatigue Syndrome: Clinical Working Case Definition,

Diagnostic and Treatment Protocols. Carruthers B et

al. JCFS 2003:11 (1): 7-115).

During the UK Guideline consultation period, at

least 40 submissions to NICE drew attention to the

importance of the Canadian Guidelines (CFS / ME:

stakeholders comments and GDG responses: see

http://www.nice.org.uk/guidance/index.jsp?action=folder & o=36179).

Those submissions came not only from patients and

support groups, but from professionals who do not

subscribe to the Wessely School (behavioural)

model and from ME/CFS charities. All made valid

points, for example:

* LocalME wrote: " (The Canadian)

Guidelines were based on the international

panel's collective extensive clinical

experience diagnosing and treating more

than 20,000 ME/CFS patients, and are

widely believed to be the most detailed

and comprehensive definition of ME/CFS in

the world. They have informed Southern

Australia as a basis for their own GP

guidance and are endorsed by scientists

here in the UK "

BRAME (Blue Ribbon Awareness for ME)

wrote: " Not to give credence (to) and

recognition of the Canadian Guidelines, the

most comprehensive clinical diagnostic

criteria, and which provide a wealth of

evidence-based advice, created by

worldwide experts on (ME/CFS) is

diabolical. One of our medical advisers

(wrote): 'The reluctance to accept the

biomedical model suggested in the

Canadian document is unhelpful'.

* Adoption of the Canadian Clinical

Guidelines would really have helped

medical professionals, not only to have the

information they need to make an accurate

diagnosis of ME/CFS, but would also give

them constructive information and skills to

help manage their patients' chronic illness.

The Canadian Guidelines manage to give a

detailed account of pharmacological

symptoms control, detailing which drugs

are most likely to help, and those with the

worst side effects. If that Guideline can do

this, then why can't this one? "

* the UK charity Action for ME wrote:

" Diagnostic criteria remains a contentious

issue, with many questioning the omission

of the Canadian criteria "

* the West Midlands Consortium wrote:

" The Canadian Case Definition was

produced by a team of international

specialists in (ME/CFS), with experience of

over 20,000 patients. These guidelines are

widely believed to be the most detailed

and comprehensive (available). By

comparison, the NICE Guidelines appear to

endorse an extraordinarily weak definition

of CFS/ME which amounts to chronic

unexplained fatigue plus one other

symptom "

* SWAME (South West Alliance for ME)

wrote: " We believe that clinical guidelines

need to go much further in describing the

range of symptoms, as do the Canadian

Clinical Guidelines "

* The ME Association wrote: " We are very

disappointed to find the GDG appear to

have totally rejected the way in which the

Canadian Guidelines have moved towards a

much tighter clinical definition that clearly

recognises the importance of subgrouping

under the ME/CFS umbrella " .

One of the world's leading researchers into ME/CFS,

Professor Leonard (see below), is on record

about the need for the Canadian Guidelines to be

used: commenting on his own group's comparison of

the Canadian Guidelines with other Guidelines,

was clear:

" The Canadian Criteria selected patients with more

physical impairment, more fatigue and weakness,

and neurocognitive and neurological symptoms. The

findings suggest that the Canadian criteria point to

(the) designating post-exertional malaise and

fatigue, sleep dysfunction, pain, neurocognitive and

autonomic / neuro-immuno-endocrine symptoms as

major criteria. The selection of diagnostic signs and

symptoms has major implications for which

individuals are diagnosed with ME/CFS and how

seriously the illness is viewed by healthcare

providers (and) disability insurers. I hope the results

of this comparison study will encourage more

physicians to use the Canadian Clinical Criteria "

(Myalgic Encephalomyelitis / Chronic Fatigue

Syndrome: An Overview of the Canadian Consensus

Document " . Bruce M Carruthers; Marjorie I van de

Sande

http://www.cfids-cab.org/MESA/me_overview.pdf ).

Dr Bell, a leading paediatrician specialising in

ME/CFS, also endorsed the Canadian Guidelines: " In

the past few years, science has made extraordinary

strides in understanding the basic mechanisms of

ME/CFS, yet little of this science has reached medical

practitioners to be used in relieving the suffering of

patients affected by the illness. It is now possible

to define abnormalities in the neurological, immune,

autonomic and neuroendocrine systems in a concise

way that can paint a portrait of this disabling illness.

The Canadian consensus definition of ME/CFS is a

concise summary of these advances and permits a

clear diagnosis for patients. (It) should be read and

studied by every medical provider "

(http://www.cfids-cab.org/MESA/me_overview.pdf ).

The GDG, however, proscribed the use of the

Canadian Guidelines.

In rejecting the use of the Canadian Guidelines, the

GDG gives as its reason: " The Canadian criteria are

based on expert opinion and not on research

evidence " , repeating this on pp 15, 16, 81, 86, 87,

155, 163 and 195 in its comments on Stakeholders'

submissions.

Another version of the reason given by the GDG is

risible: " The Canadian Guideline is a consensus

document and does not provide an evidence-base for

their guidance " .

Not only is it demonstrably untrue that the Canadian

Guideline provides no evidence-base for its guidance,

(which is based on world-class evidence and contains

237 references), but for the GDG to reject the

Canadian Guideline because it is a " consensus "

document demonstrates the double standards and

fundamental bias employed by the GDG, who

themselves used " consensus " in the formulation of

their own Guideline:

" Aware that the GDG might find difficulty in reaching

agreement on some of the more controversial issues,

NICE set up two new procedures to help us make

our recommendations: a formal consensus

method and consultation with a wider group

nominated by stakeholders " (Dr Fred Nye, GDG

member: J Inf 2007:55:6:569-571). That consensus

was used was also confirmed by the GDG itself:

" Consensus was used " (page 36 of the GDG

Comments on Stakeholder submissions on Chapter

2).

It is perhaps relevant that Professor

Pinching (the patients' " Champion " ) who in the

Guideline Acknowledgements is singled out by the

GDG for special thanks and who, according to NICE,

was instrumental in formulating the GDG's remit --

and who is lead adviser on " CFS/ME " to the UK

Department of Health and who was responsible for

the setting up of the " CFS " Centres that will deliver

only behavioural interventions for " CFS/ME " --

advised NICE that: " The Canadian definition has not

been tested or validated as a set of criteria " .

The Canadian Criteria advocate the subgrouping of

patients into three distinct categories (autonomic,

which includes cardiovascular; inflammatory and

endocrine symptoms), but the GDG ignored the many

calls for subgrouping of " CFS/ME " and subsumed all

states of " medically unexplained fatigue " – in which

it includes ME/CFS -- into a single somatoform

construct and based its management

recommendation on this heterogeneous population,

claiming -- as the Wessely School claims -- that

there is no evidence of the need to subgroup

" CFS/ME " .

Given the extent of the international evidence that

subgrouping is essential, such a statement by NICE

is insupportable.

In support of its recommended management regime,

NICE relied mostly on the Oxford criteria for " CFS "

which were published in 1991 by psychiatrists of the

Wessely School and which specifically include in their

own case definition of " CFS/ME " those patients with

pre-existing psychiatric disorder and exclude those

with neurological disease (Sharpe M, Wessely S et

al. JRSM 1991:84:118-121).

The need for subgrouping of " CFS " (known as

" CFS/ME " by UK Departments of State whose

advisers are Wessely School psychiatrists and

adherents)

In response to representations from Stakeholders

pointing out the urgent need for subgrouping (for

example, the patients' representative group BRAME

[blue Ribbon Awareness for ME] was clear:

" If sub-groups were identified it would help in

offering appropriate treatment " ), the GDG's

invariable response was:

" The evidence reviewed in this guideline does not

allow us to distinguish between these groups when

making recommendations " (GDG response to

Stakeholders' comments on chapter 5, page 56 of

279).

This mantra is repeated throughout, for example:

" No research evidence was found for defined

subgroups or different management strategies "

(GDG Comments, page 455 of 575); " The GDG did

not find evidence of sub-groups " (GDG Comments,

page 459 of 575). Where subgrouping is referred to,

the GDG seems only to consider those who are mildly

affected, those who are moderately affected, or

those who are severely affected, and not the distinct

clinical subgroups.

In 1997 et al were clear about the psychiatric

bias in " CFS/ME " research: in a Review article,

et al stated that flaws in the case definition

and in the design of (mostly UK) epidemiological

studies have " led to inaccurate and biased

characterisation of CFS " which incorrectly favour

a psychiatric view of the disorder.

et al noted that the Australian and British case

definitions do not consider pre-existing psychiatric

disorder to be exclusionary for a diagnosis of " CFS "

and stated: " the erroneous inclusion of people

with primary psychiatric conditions in CFS samples

will have detrimental consequences for the

interpretation of both epidemiologic and

treatment efficacy findings. Until more

differentiated subgroups are developed, it will be

exceedingly difficult to identify characteristics that

are common for all people with the diagnosis of

CFS " (American Psychologist 1997:52(9):973-983).

Leonard is one of the foremost researchers

into the disorder. He is Professor of Psychology and

Director, Centre for Community Research, De

University, Chicago; he is also Vice President of the

International ME/CFS Association and is a member of

the CFS Advisory Committee to the US Secretary of

Health and Human Services.

Subgrouping of " CFS/ME " is important and necessary

and the extensive literature supporting the need for

it cannot be denied.

Prominent US researchers, including Lerner,

Arnold Peckerman, Natelson and

Cheney (see below) have found that one subgroup

contains people with ME/CFS who have a particular

form of cardiomyopathy, as described by Cheney

(Professor of Medicine at Capitol University,

Washington DC, see below).

Wessely, however, does not agree: in

correspondence arising from his article " Chronic

fatigue syndrome: Symptoms and Syndrome " (ls

of Internal Medicine 2001:134:9S:838-834, in which

he wrote:

" [There] is a debate about subgroups. Some of

the desire to split the chronic fatigue syndrome

into subgroups is driven by emotion " ),

Wessely said: " What matters is the evidence. Here I

am on firmer ground. The approach that we have

developed (CBT and GET) is safe and cost effective

and it represents a reasonable way forward, reducing

symptoms and disability. All I can say is that the

results of our approach have really made a

difference. So I can sleep easy at night when it

comes to treatment – I know we have done more

good than harm. You mention the views of

Cheney, but I must say I disagree profoundly with

them – and more importantly, so does every

neurologist I have ever met. All I know is that I

am quietly proud of what our group has achieved

over the years " (personal communication, 17th May

2001).

However, Wessely is not a cardiologist, nor a

neurologist, nor an immunologist, nor a virologist,

nor an expert in gene expression. He is a

psychiatrist.

This is important, because the current issue of the

BMJ (2nd August 2008:337:263) is clear that

" experts " must not succumb to the temptation to

speak outside their own core area of expertise:

" Staying within your area of expertise is one of the

key rules highlighted this week in a new GMC guide

for expert witnesses. Another pitfall it warns

against is being too partisan and too wedded to

pet theories. Where there is a range of opinion on a

subject, (an expert) must outline this and explain

how he reached his own views " .

It is a matter of record that Wessely promotes

himself as a " world expert in the field of medically

unexplained illnesses including Chronic Fatigue

Syndrome " (PRISMA Company Information, 2001).

While it remains the case that the precise aetiology

of ME/CFS is as yet unknown (as is the case in many

other diseases), it is incorrect that the cause of the

symptomatology is unknown. For example, there is a

significant literature on evidence of hypothalamic-

pituitary-adrenal (HPA) axis dysfunction in ME/CFS,

which results in many of the symptoms. What is not

yet known is what causes the HPA dysfunction.

Despite Wessely's denial, a significant percentage

(at least 20%) of people with ME/CFS as distinct

from " CFS/ME " die from cardiac failure (Causes of

Death Among Patients with Chronic Fatigue

Syndrome. L et al. Healthcare for Women

International: 2006:27:615-626).

Although denied by the GDG, there is abundant

documented evidence of cardiac and vascular

problems in ME/CFS (see below), yet the GDG

stipulates that: " signs and symptoms of

cardiorespiratory disease should not be attributed

to CFS/ME " (52 page version, page 15:1.2.1.4) and

instead refers to " perceived exertion " (52 page

version, page 30:1.6.2.17).

The ignoring by NICE of this important subgroup is

just one of the many deficiencies of the Guideline,

some of which become more apparent when the

Guideline is compared with the advice provided for

ish clinicians about the same disorder.

Comparison of the ish Good Practice

Statement with the NICE Guideline for England,

Wales and Northern Ireland

Whilst NICE is overly inclusive about what

constitutes " CFS/ME " , it is unduly proscriptive about

which interventions apart from psychotherapy may be

used in management.

The position adopted by NICE should be compared

with that taken about the same disorder in Scotland

( " ish Good Practice Statement on ME/CFS: A

Guide for GPs to use in the consulting room " . Dr

Gregor Purdie, on behalf of the ish Government;

produced in consultation with ish Medical

Practitioners, people with ME in Scotland and their

representatives, ME charities and support groups and

professionals in health, social care and research;

23rd July 2008).

The ish Good Practice Statement (SGPS) is

very different from the NICE Guideline:

" The purpose of this ish Good Practice

Statement on ME/CFS is to provide general

practitioners with a simple, straightforward document

that can be easily used in the consulting room.

National and international debate is ongoing as to

the appropriate terminology but for the purposes of

this statement we will use the composite ME/CFS,

the term recommended by the ish Public Health

Network.

" The NHS has recognised that the physical symptoms

can be as disabling as multiple sclerosis, systemic

lupus erythematosus, rheumatoid arthritis,

congestive heart failure and other chronic conditions

and that the illness places a substantial burden on

people with the condition, their families and carers,

and on society.

" ME/CFS is experienced by patients as a range of

symptoms and it is therefore necessary to adopt a

holistic approach to treatment and care. Empathetic

listening is vital.

" Some people are described as being severely

affected by ME/CFS. It is estimated that 25% will

fall into this category at some stage in their illness.

They will often spend periods of time bed-bound,

housebound, or wheelchair bound, and perhaps be

unable to tolerate movement, bright light, noise,

certain scents or chemicals (including prescribed

drugs). Neurological symptoms can be extreme --

with for example, difficulty swallowing requiring

nutritional support, and the investigations of vitamin

deficiencies " .

The ish statement informs clinicians that people

with ME/CFS " are often sensitive to the side-effects

of drugs, particularly anti-depressants, anaesthetics

and those which act on dopaminergic transmission

(eg. metoclopramide / Maxalon). Sensitivities and

intolerances to various foods are often experienced

by people with ME/CFS and contribute to

gastrointestinal problems " .

Advised by the Wessely School, the NICE Guideline

states that there is no evidence of adverse reactions

to prescribed medication, or of multiple chemical

sensitivity (MCS): " No research evidence was found

to support the experience of some people with

CFS/ME that they are more intolerant of drug

treatment and have more severe adverse / side

effects " (52 page version of Guideline, page 18,

section 1.4.1.2). Such a statement ignores the

compelling evidence to be found in the work of

Pall, Professor of Biochemistry and Basic

Medical Sciences, School of Molecular Biosciences,

Washington State University (for an explanation of

his work, see

http://www.meactionuk.org.uk/Resume_of_Pall_MCS_paper_-_August_2002.htm

It also disregards the fact that since 2000, MCS is

listed in the ICD (ICD-10-SGBV, version 3.1:T78.4).

NICE also specifically proscribes the use of vitamin

supplementation.

The ish Statement advises that ME/CFS

commonly follows some form of viral infection, and

that it can be precipitated by " vaccinations, toxins

(and) pesticide exposure " .

Despite the large body of literature documenting

viral persistence in ME/CFS, the NICE GDG did not

include a virologist. Only those professionals who

believe in the behavioural model of " CFS/ME " were

chosen to be GDG members, as confirmed by NICE:

" We had a large number of nominations for this

guideline development group from professional

organisations wishing to contribute (but) we gave

preference to those with day to day clinical

experience for managing this condition " (letter dated

23rd December 2004 from Turnbull, Chief

Executive, National Collaborating Centre for Primary

Care to Dr Shepherd, Medical Director, ME

Association, rejecting his offer to be on the GDG).

Since the only NHS management is behavioural

interventions, restricting the choice of GDG members

to those engaged in delivering such interventions

meant that the Guideline's management

recommendations were a foregone conclusion.

Importantly, the GDG made no mention of the fact

that the Parliamentary Under Secretary of State The

Lord Warner confirmed in writing on 11th February

2004 in a letter to the Countess of Mar that people

with ME/CFS (also known as Postviral Fatigue

Syndrome and classified as such by the World

Health Organisation [WHO] in the International

Classification of Diseases ICD-10 G93.3) are not

permitted to be blood donors.

Lord Warner was unambiguous: " We have checked

with the National Blood Service and they have

provided the following information. The NBS

guidelines on donor selection on ME refer to those

on Post Viral Fatigue Syndrome. The Guidance is:

defer from blood donation until recovery. The

underlying logic is that this condition is possibly

viral and therefore the NBS cannot accept the risk

of possible transmission by blood. Since the

condition is very variable and sometimes prolonged,

it could become a lifetime ban in any particular

case. I have copied this letter to the House (of

Lords) library " .

Notably, those with behavioural disorders are not

prevented from being blood donors.

The ish Statement continues: " Key symptoms

(include) exercise-induced muscle fatigue;

post-exertional malaise; pain that is often persistent

and difficult to control (and) a general feeling of

ongoing malaise " .

Again in contrast, the NICE Guideline relies heavily

on Random Controlled Trials (RCTs) produced by the

Wessely School, whose own case definition does not

include exercise-induced muscle fatigue or

post-exertional malaise.

The ish Good Practice Statement is

unambiguous: " Other symptoms (include)

dysequilibrium; autonomic dysfunction, disturbed

thermoregulation, night sweats and heat sensitivity;

sensory disturbances; hyperacusis and/or

photophobia; arthralgia; irritable bowel-type

symptoms (and) alcohol intolerance, drug and

chemical sensitivities " .

It is notable that psychiatrist Professor White,

a key member of the Wessely School, advised NICE

that bowel problems are not a feature of " CFS/ME " :

" bowel symptoms are not part of CFS/ME " (St

Bartholomew's Hospital Chronic Fatigue Service

Stakeholder Comments on Chapter 6, page 143).

There is a significant literature documenting

gastrointestinal problems in ME/CFS (which the

Wessely School refers to as " CFS/ME " ), so it is

disturbing that Professor White's Unit seems to be

unaware of it, especially as he is lead adviser on

" CFS/ME " to the Department for Work and Pensions.

It is not clear why a psychiatrist should be advising

the DWP about a multi-system neuro-immune

classified organic disorder.

The ish Statement differs markedly from the

NICE Guideline in advising ish clinicians that

appropriate investigations may include testing for

adrenal insufficiency; immunodeficiency and

autonomic function, and that tests may include

nuclear medicine scans (MRI); muscle biopsy and

serum 25-hydroxyvitamin D status.

These are specifically proscribed by NICE for patients

with the same disorder in England, Wales and

Northern Ireland.

Regarding the management regime recommended by

NICE as the primary (indeed only) treatment option,

the ish Statement could not be more different.

Referring to graded exercise therapy (GET), it states:

" The following treatments have a varying rate of

success and in some cases have been harmful to

individuals. Graded exercise therapy makes use of

an exercise programme involving a progressive

increase in aerobic exercise on a day to day basis

(and) is intended to restore physical fitness which

has declined due to inactivity imposed by ME/CFS.

Cognitive behavioural therapy (CBT) is a

psychological intervention.

" In England, there are special clinics which offer

these therapies as specific treatments for ME.

There has been much concern expressed about

the evidence-base for these treatments. In

Scotland, these treatments are being evaluated in

the PACE trial (a Medical Research Council trial run

by Wessely School psychiatrists) which is at present

underway in Edinburgh. It would be prudent,

therefore, to await the evaluation before making

any pronouncements on the specific place of these

therapies " .

In contrast, NICE pre-empted the results of the same

trials in England and, further supporting the

widely-held expectation that, like the NICE

Guideline, the outcome of the trials is a foregone

conclusion, recommended the national

implementation of behavioural interventions that are

promoted by the Wessely School.

Evidence of cardiovascular dysfunction in

ME/CFS that the GDG was directed to disregard

NICE claims that there is little good research

evidence for most aspects of " CFS/ME " apart from the

psychosomatic (behavioural) model put forward by

the Wessely School (GDG comments on Chapter 2).

Although NICE acknowledged the need for

" consensus " methods and paid lip-service to this

need, the GDG largely ignored the expert patients'

consensus, claiming that it was " biased " .

Not only did NICE ignore the expert patients'

evidence, as well as the evidence of clinicians and

notable biomedical researchers who challenged the

basis of the Wessely School's beliefs about the

nature of ME/CFS, it also ignored the significant body

of research which shows that patients with ME/CFS

may be in a particular form of heart failure and

should not, therefore, be subject to incremental

aerobic exercise as recommended by NICE.

It is notable that the draft Guideline of September

2006 advised patients and clinicians that an exercise

programme should not be maintained if there is

active infection, but that this explicit warning to

cease exercising during active infection was removed

from the final Guideline (cf Draft Guideline page 142

and Full Guideline page 150).

Illustrations of cardiovascular

dysfunction in ME/CFS include the following:

1957

One of the most useful and important descriptions of

ME is that of Dr Wallis as contained in his

doctoral thesis (An Investigation into an Unusual

Disease seen in Epidemic and Sporadic Form in a

General Practice in Cumberland in 1955 and

subsequent years. Lachlan Wallis. Doctoral

Thesis, University of Edinburgh, 1957). For a

summary, see

http://www.meactionuk.org.uk/Vade_MEcum.htm .

Wallis particularly noted myocarditis (heart rate

was accelerated during the illness), with

dyspnoea on slightest exertion. The post-mortem

histopathology report from one (female) case stated:

" There are in the entire diencephalon, particularly

round the third ventricle, numerous small

haemorrhages, which extend into the adjacent parts

of the mid-brain. Similar haemorrhages can be seen

in the corpora mamillare. The haemorrhages are

mostly around the small vessels but some are also

to be seen in the free tissue. This is a significant

finding. "

Comparison of the Wallis findings

with other published findings

The post-mortem histopathology report in Wallis'

thesis was particularly interesting, given the

subsequent documented evidence of vascular

abnormalities and impaired blood flow in ME/CFS. For

example, references in one textbook of ME/CFS to

vasculopathy include the following:

" lymphocytes in the cerebrospinal fluid congregate in

the perivascular (Virchow Robin) spaces of the

brain…these findings do suggest that the disease

may involve the perivascular spaces of the brain

" dilatation of the Virchow Robin spaces could also

suggest intracranial arterial or periarterial pathology,

in particular, one would expect to find a congregation

of lymphocytes in the perivascular spaces around the

central nervous system arteries…(Wallis) revealed

an artefact that is in an anatomical position similar

to that suggested by MRI studies

re: the Los Angeles 1934 epidemic: " The blood

vessels throughout the nervous system were

distended with red blood cells…the most

characteristic change was infiltration of the blood

vessel walls " (The present consensus on MRI in

ME/CFS. Royce J Biddle. In: The Clinical and

Scientific Basis of ME/CFS. ed: BM Hyde; The

Nightingale Press, Ottawa, Canada 1992).

Other references to vasculopathy in ME/CFS in the

same textbook include:

page 42 (Chapter 5 / BM Hyde): " We routinely

observe patients with severely cold extremities and a

visible line demarcating the cold from the area of

normal skin temperature. The fact that the loss of

normal blood flow may be persistent has been

indicated by Gilliam (1938) "

page 62: " Patients will complain of severe blanching

of their extremities, nose, ears, lower arms and

hands as well as lower legs and feet. Observation

will often reveal a blanched clearly demarcated line

separating warm from icy cold tissue. The whitened

extremities may persist for hours and can be

extremely painful "

page 70: " The haemorrhages are mostly around

small vessels, but some are also to be seen in the

free tissue "

page 73: Hyde discusses the occurrence of Raynaud's

Disease in ME/CFS: " This is common in ME/CFS.

These acute Raynaud's Disease changes are visible "

page 89: (Chapter 8 / ): " A liver

biopsy showed a vasculitis of the liver "

paqe 91: " Liver Function Tests are sometimes

abnormal and signify a vasculitis of the liver "

page 250: (Chapter 23 / Jay Goldstein): " SPECT

scanning may justify vasodilator therapy with calcium

channel blockers "

page 286: (Chapter 28 / EG Dowsett): " ME is a

multisystem syndrome including nervous,

cardiovascular, endocrine and other involvement.

Symptoms and Signs (table 2): Vasculitic skin

lesions, autonomic dysfunction, especially circulation

and thermoregulation "

page 376: (Chapter 42: Hyde and Jain: Cardiac and

Cardiovascular Aspects of ME/CFS): reference is

made to " frequent vasomotor abnormalities "

page 377: " vasomotor disturbances were almost

constant findings, with coldness and cyanosis. It was

the impression of most observers that a generalised

disturbance of vasomotor control occurred in these

patients "

page 377: " Findings included sinus tachycardia,

abnormal T waves in two or more leads (and)

prolongation of Q-T interval "

page 377: " Myocarditis in the acute phase: the heart

rate was accelerated (and) tachycardia was

considered to be a diagnostic feature. In four cases

there was a persistent rise in blood pressure (which)

slowly lowered over a period of many months "

page 378: " Cardiovascular symptoms: angina-like

pain; vascular headache; orthostatic hypertension;

oedema; dyspnoea; transient hypertension (note

that on page 42, Hyde states about blood pressure

regulation: " Some seem to be unable to adjust

blood pressure with body activity, resulting in high

blood pressure on modest activity and very low

pressure when reclining " )

Page 378: referring to Professor Behan's CIBA

lecture in 1988: " using SPECT scan techniques, his

team was regularly able to demonstrate

micro-capillary perfusion defects in the cardiac

muscle of ME patients "

page 380: " These chronic ME/CFS patients

complain of severe chest pain and shortness of

breath as if suddenly stopped by an invisible

barrier "

page 381: " Arrhythmias are frequently noted in the

first few weeks of illness, then decrease in

frequency, only to return in a chronic form 20 years

later "

page 433: (Chapter 49 / Ismael Mena): referring to

the need for SPECT scans in ME/CFS patients, Mena

states: " The accuracy and reproducibility of these

measurements are justification to evaluate

cerebral perfusion abnormalities in patients with

ME/CFS. Most probably, temporal lobe perfusion

defects may fingerprint primary inflammatory

changes or secondary vascular impairment in

these patients "

(It is notable that SPECT scans are specifically

proscribed by NICE).

page 437: " the diminished uptake of this oxime can

be interpreted as due to a) diminished rCBF (regional

cerebral blood flow), inflammatory regional

changes (present in 71% of patients studied) "

page 598: (Chapter 65 / LO Simpson): " if the stasis

did not resolve, focal lesions of ischaemic necrosis

would develop "

page 673: (Chapter 75 / J ): Dr Jon is a

world expert on fibromyalgia (which may be a

comorbidity with ME/CFS: " Fibromyalgia appears to

represent an additional burden of suffering amongst

those with ME/CFS " . Buchwald D et al. Rheum Dis

Clin N Am 1996:22:2:219-243) and says about the

prevalence of vasculitis: " It is apparent that some

patients with fibromyalgia also exhibit vasculitis

with a frequency that has caught the attention of

clinicians " .

Wessely disagrees, asserting that fibromyalgia (FM),

like ME, is but part of a single somatoform

(behavioural) disorder (Lancet 1999:354:936-939)

and consequently FM is included within " CFS/ME " in

the MRC trials, even though FM is classified as a

quite separate disorder by the World Health

Organistion (ICD-10 M79).

Furthermore, the National Fibromyalgia Association's

FAME (Fibromyalgia Assessment, Management and

Education) programme has received CME

accreditation (continuing medical education) from the

American Academy of Family Physicians

(http://www.FMaware.org ).

Other references in the literature

to cardiovascular problems in ME/CFS

1976

From the earliest reports of ME/CFS, autonomic

vasomotor instability has been noted (AM Ramsay,

Update: September 1976:539-541).

1984

There have been many reports of impaired bloodflow

in the microcirculation (LO Simpson,

NZMJ:1984:698-699).

1988

" Evidence of cardiac involvement may be seen:

palpitations, severe tachycardia with multiple

ectopic beats and occasional dyspnoea may occur

and are quite distressing. It is of great interest

that some patients have evidence of myocarditis "

(Behan P. Crit Rev Neurobiol 1988:4:2:157-178).

1989

" The data are compatible with latent viral effects

on cardiac pacemaker cells, or their autonomic

control, and skeletal muscle, that are unmasked

by the stress of exercise " (Montague TJ et al. Chest

1989:95:779-784).

1989

" Persistent viral infections impair the specialised

functions of cells. Evidence of persistent

enterovirus infection has been found in both

dilated cardiomyopathy and in myalgic

encephalomyelitis. Immunological and metabolic

disturbances in ME may result from chronic infection,

usually with enteroviruses, providing the organic

basis of the postviral fatigue syndrome. This

condition is charcterised by recuperation through

rest. The myocardium, however, cannot rest –

except terminally " (NR Grist. BMJ 1989:299:1219).

1990

" A significant group have cardiac symptoms "

(Professor Behan, Cambridge Conference

Report, 17th March 1990; ME Association Medical

Update 1990: 2).

1990

" There is a high incidence of cardiomyopathy in

CFS patients " (Dr Jay Goldstein, Director of the CFS

Institutes, Anaheim Hills; member of the Faculty of

the Department of Psychiatry, University of

California; CFIDS Reporter, Oregon, October 1990).

1991

" The patient with Post-viral fatigue syndrome

(ME) is referred to a cardiologist almost always

because of chest pain. In viral pericarditis, as with

ME, there is now abundant evidence that the

disease process arises from an abnormal

response to a viral infection.

Chest pain is variable in character. It is sometimes

severe, sharp and stabbing, or it may be dull and

aching. It is unrelated to exertion, although the

patient frequently feels the pain to be worse after a

day of increased physical activity. The pain may

last for several hours or even days. It frequently

occurs centrally but even in the same patient may

recur on a different occasion in the right or left chest

or the back. It is commonly aggravated by sudden

movement, change of posture, respiration or

swallowing.

Palpitations are frequent, with sinus tachycardia

being a common and troublesome symptom. The

diagnosis of the cause of chest pain in ME rests

almost entirely on careful clinical evaluation.

Pericarditis may continue or recur for many years

and, like ME, be a distressing and debilitating

illness. There is alas no way of predicting how long

the condition will persist, and no reliably successful

means of treating it " (Post-viral Fatigue Syndrome

and the Cardiologist. RG Gold. In: Postviral Fatigue

Syndrome. Ed: and Mowbray.

Wiley & Sons, 1991).

1993

Evidence of repetitively negative to flat T waves on

24-hour ECG monitoring was found in some ME/CFS

patients (Lerner AM et al. Chest

1993:104:1417-1421).

1994

Abnormal left ventricular dynamics (i.e. an

abnormal pumping mechanism) were

demonstrated in ME/CFS patients, including

abnormal wall motion at rest; dilatation of the left

ventricle, and segmental wall motion abnormalities

(Dworkin HJ, Lerner AM et al. Clinical Nuclear

Medicine 1994:19:8:675-677).

1994

" As with any chronic inflammatory condition

affecting the central nervous system, the

T2-bright foci on MR (magnetic resonance) in

ME/CFS may represent perivascular cellular

infiltrate and / or reactive demyelination of the

surrounding white matter….these abnormalities

may reflect the result of a vasculopathy specifically

involving the small vessels of the cerebral white

matter; indeed, the distribution of lesions on MR in

ME/CFS is similar to that observed in occlusive

arteriolar disease of any origin.

The cortical defects measured with SPECT may

result from decreased flow through cortical

arterioles owing to vasculitis. Specifically, on the

basis of our observations, the white matter

abnormalities seen on MR images may represent

chronic demyelination, which appears to be

irreversible " (Detection of Intracranial

Abnormalities in Patients with Chronic Fatigue

Syndrome: comparison of MR imaging and SPECT.

Schwartz RB, Komaroff AL et al. Am J Roentgenol

1994:162:935-941).

1995

" The use of cardiopulmonary exercise testing is not

only valid and reliable, but also serves as an

objective indicator for assessing disability. Maximal

cardiopulmonary exercise testing provides two

objective markers of functional capacity. The first is

maximal oxygen consumption. The most important

determinant of functional capacity is not maximal

oxygen consumption, but anaerobic threshold.

Typically ME/CFS patients achieve less than 80%

of predicted maximal oxygen consumption with an

anaerobic threshold lower than 40% of predicted

peak oxygen consumption levels. In ME/CFS

patients, we have not found re-conditioning to be

possible. In fact, attempts to re-condition patients

consistently results in exacerbation of

symptomatology.

Cardiopulmonary exercise testing can be used to

provide ME/CFS patients with another objective

marker that will aid them in obtaining disability

status " (SR . JCFS 1995:1:3-4:127-129).

1996

At the State of Massachusetts educational workshop

given by Professor Cheney, evidence was

presented of the complexity of ME/CFS (referred to

as " CFIDS " , or Chronic Fatigue and Immune

Dysfunction Syndrome).

According to Cheney, 80% of ME/CFS patients display

medication and environmental sensitivities; there is

evidence of lymphatic involvement, with the thoracic

duct being tender, and the swollen areas on the neck

or upper chest being a back-up of lymphatic fluid.

Cheney biopsied 16 digits of people with ME/CFS

and found a vasculitis not uncommon in immune

activation and similar to that which is found in SLE

/ systemic lupus erythematosus (The

Massachusetts CFIDS Update).

1997

" Myocarditis was a common symptom in an

analysis of 1,000 patients of ME/CFS who were

seen in Glasgow over the past 20 years. We were

struck by the often-occurring association of patients

who develop ME/CFS with acute chest pain

resembling a coronary thrombosis.

On subsequent clinical follow-up, all these patients

had a clinical course that was indistinguishable from

patients who presented with Syndrome X. Nuclear

magnetic resonance spectroscopy studies of skeletal

muscle in patients with Syndrome X show

abnormalities that are identical to those found in

patients with ME/CFS.

We, in examining muscle biopsies of patients with

ME/CFS, showed an increase in calcium ATPase

activity in skeletal muscles. These data strengthen

the relationship between ME/CFS and Syndrome X

and suggest that an increased energy expenditure,

with a consequent reduction of intra-cellular ATP

(adenosine triphosphate) and an increase in ATPase

activity could account for the abnormalities in these

two conditions.

Thallium cardiac scans (thallium-210 SPECT scans)

in patients with ME/CFS revealed moderate

defects in the left ventricle " (Arguments for a role

of abnormal ionophore function in CFS. A Chaudhuri

et al. In: Chronic Fatigue Syndrome. Ed: Yehuda and

Mostofsky; Plenum Press, New York, 1997).

1997

" We report the prevalence of abnormal oscillating T

waves at Holter monitoring in a consecutive case

series of ME/CFS patients from an infectious

diseases centre. Every ME/CFS patient, but only

22.4% of the non-ME/CFS patients, showed

abnormal oscillating T wave flattenings or

inversions at Holter monitoring. Abnormal cardiac

wall motion at rest and stress, dilatation of the left

ventricle, and segmental wall abnormalities were

present.

Left ventricular ejection fractions, at rest and with

exercise, as low as 30% were seen in ME/CFS

patients. The abnormal (results) which we confirm

here appear to be an essential element to the

pathologic physiology of the cardiomyopathy of

ME/CFS " (Cardiac Involvement in Patients with CFS

as Documented with Holter and Biopsy Data in

Michigan, 1991-1993. AM Lerner et al. Infectious

Diseases in Clinical practice 1997:6:327-333).

This research was summarised by Dr PD Corning,

having been reviewed and approved by Dr Lerner:

" Dr Lerner, an Infectious Diseases specialist at

Wayne State University, and his colleagues have

found evidence that ME/CFS may be caused by a

persistent (virus) infection of the heart. This

research is significant and well-documented.

In this study, 100% of the ME/CFS patients

showed abnormal oscillating T waves at 24-hour

Holter monitoring and 24% showed weakened

function on the left side of the heart (the side that

pumps oxygenated blood to all the body except the

lungs). The data showed that patients exhibited

evidence of cardiomyopathy, or disease of the

heart muscle.

This finding is so consistent (and) it distinguishes

ME/CFS from those with fatigue of unexplained

origin. This work offers hard evidence to back up

ME/CFS patients' much disbelieved claim that

exercise is harmful and causes disease

progression in ME/CFS.

In many cases, the resulting disease process is

progressive. (The virus) attacks the heart tissue

producing exercise intolerance, the hallmark of

ME/CFS. These researchers have backed up their

work with biopsies of the cardiac tissue in ME/CFS

patients. They found heart muscle

disorganisation, muscle fibre disarray, abnormal

formation of fibrous tissue in place of heart muscle

cells, fat infiltration and increases in mitochondria

within heart muscle cells.

All these results are indicative of cardiomyopathy.

The weakened heart is aggravated by physical

activity, accounting for post-exertional sickness so

common in this disease. When the heart muscle

tissue is infected, overactivity causes death of

cardiac tissue and disease progression.

This is in direct conflict with conclusions that

ME/CFS symptoms are caused by underactivity

due to a sedentary lifestyle. Dr Lerner and

associates have also documented abnormal fraction

ejection in ME/CFS. Normally, over half the blood in

the left ventricle is ejected when the left ventricle

contracts. In Dr Lerner's subjects, the ejection

fraction is decreased. Some patients had a

reduced ejection fraction at rest. Others had an

ejection fraction that decreased during exercise

from 51% to 36%. In a normal subject, the

ejection fraction will rise over 5% during exercise.

Declining ejection fractions are not seen in normal

persons leading sedentary lives " .

The full summary is at

http://www.ncf.ca/ip/social.services/cfseir/naneir/news/28FEB98.html

1998

At the Fourth International AACFS Research and

Clinical Conference held in Massachusetts in October

1998, Arnold Peckerman and Natelson et al

presented evidence of a disorder of the circulation in

ME/CFS. As a group, patients with ME/CFS displayed

similar cardiovascular function status on most of the

parameters, but a lower stroke volume was found to

be highly predictive of illness severity.

These findings indicate a defect in the higher control

modulation of cardiovascular autonomic control. In

the more severe cases, situations may arise

where a demand for blood flow to the brain may

exceed the supply, with a possibility of ischaemia

and a decrement of function (CFS Severity is

Related to Reduced Stroke Volume. Peckerman et al.

AACFS, October 1998).

1999

et al reported that perfusion defects seen in

thallium cardiac scans of ME/CFS patients were

unlikely to be explained by occlusive coronary vessel

disease and that in their studies (as well as in other

independent studies), cardiac thallium SPECT scans

were shown to be abnormal in the majority of

patients with ME/CFS and perfusion defects were

common.

Cardiac SPECT scanning is a nuclear medicine

technique used to identify regions of

under-perfused myocardial tissue (A Possible Cell

Membrane Defect in Chronic Fatigue Syndrome and

Syndrome X. Walter S et al. In: Kaski JC

(Ed). Chest pain with normal coronary angiogram:

pathogenesis, diagnosis and treatment. Kluwer

Academic Publishers, London 1999: chapter

13:143-149).

1999

" This study examined the cardiovascular response to

orthostatic challenge. Among subjects who

completed the test, those with ME/CFS had higher

heart rate and smaller stroke volume than

corresponding control subjects. These data show

that there are baseline differences in the

cardiovascular profiles of ME/CFS patients when

compared with control subjects " (La Manca JJ et al.

Clinical Physiology 1999:19:2:111-120).

2000

" The results of this study show enhanced cholinergic

activity in the peripheral microcirculation of patients

with ME/CFS. Many of the symptoms of ME/CFS,

such as temperature sensitivity, gastrointestinal

difficulties, problems with sleep, and orthostatic

intolerance, are consistent with altered cholinergic

activity. Our findings might have important

implications for features of ME/CFS that involve

vascular integrity " (V Spence et al. Am J Med

2000:108:736-739).

2001

" Convincing evidence of cardiovascular impairment

can be demonstrated " (Research Update

presentation to the Alison Hunter Memorial

Foundation Third International Clinical and Scientific

Conference on ME/CFS held in Sydney, Professor Mina

Behan, University of Glasgow).

2001

According to Streeten, Professor of

Endocrinology at Upstate Medical Centre in Syracuse,

NY: " Inconsistently excessive increases in heart

rate were found in ME/CFS patients, in whom

venous compliance was significantly reduced (and

in whom) delayed orthostatic hypotension was

clearly demonstrable, implying impaired sympathetic

innervation. Excessive lower body venous pooling,

perhaps by reduced cerebral perfusion, is involved in

the orthostatic component in these patients "

(Streeten DH. Am J Med Sci 2001:321:3:163-167).

2001

h Ryll, Assistant Clinical Professor of Medicine,

Division of Infectious and Immunology Diseases,

University of California, believes that in ME/CFS

there is an infectious venulitis: " Troublingly (in the

literature) very few vascular features were

mentioned. I have followed these patients since

1975. Because of this, I have learned all the

nuances, all the signs and symptoms of the

disease. In studying this disease, one must always

have an open mind. This disease teaches the

physician to be humble.

The extremity discomfort is often described as a

burning, searing sensation. Numbness and tingling of

the extremities is common (and) cases have

spontaneous bruises that occur without any injury.

The disease is frightening to patients because of

its severity and its many unusual features.

Physicians are not trained to diagnose an illness

that encompasses so many signs and symptoms.

Two common statements patients make are: 'I

hurt all over' and 'I am going to die'. During

relapse, many can be totally helpless and unable

to care for themselves. Dizziness often occurs and

for some patients, it is constant. They are

uncoordinated and lurch about. They state that their

legs just give way, causing them to fall.

The autonomic nervous system that controls blood

vessels is deranged in the disease. Sweating,

flushing, icy and blue hands and feet, hot sweaty

hands, red and blotchy hands are common. Pain

can be the most severe aspect of this disease.

There is partial paralysis of the gastrointestinal

tract (which) can lead to nausea. Small veins can

suddenly rupture. Deep veins can remain

inflamed and are not visible on the surface. An

electromyogram is frequently abnormal, showing

damage to nerves. The MRI brain image often

reveals evidence of demyelination. A SPECT scan

invariably shows impairment of brain blood

circulation. Muscles may be damaged but do not

waste away. There is currently no treatment that

can cure this disease. Treatments are geared to

making life more bearable "

(http://home.tampabay.rr.com/lymecfs/ryll.htm ).

2001

" As a group, the ME/CFS patients demonstrated

significantly lower cardiovascular as well as

ventilatory values compared with the control

group. These results indicate either cardiac or

peripheral insufficiency embedded in the

pathology of ME/CFS " (Inbar O et al. Med Sci

Sports Exerc 2001:33:9:1463-1470).

2001

" The haemodynamic instability score differed

significantly between ME/CFS and other groups "

(Naschitz JE et al. Semin Arthritis Rheum

2001:31:3:199-208).

2002

According to Rowe, Professor of Paediatrics at

s Hopkins and an ME/CFS specialist: " Several

groups have shown that ME/CFS patients have

abnormal regulation of heart rate and blood

pressure, as well as high rates of allergic disease.

About a third of ME/CFS studies have identified low

urinary and serum levels of cortisol " (Co-Cure MED:

3rd May 2002; see also C Rowe, Journal of

Paediatrics 2002:140:387-388).

2003

" The main symptom of the ME/CFS patient, i.e.

chronic fatigue that is greatly exacerbated by

even minor effort, is similar to that of a patient

with left ventricular dysfunction. We performed

nuclear ventriculography (MUGA / radioisotopic

multiple gated acquisition used to perform a series

of dynamic studies of the heart to assess for

evidence of abnormalities with myocardial function)

stress tests in ME/CFS patients and controls. During

maximal exercise, ejection fraction (EF) increased

in controls but declined in ME/CFS patients. The

decreases tended to be greater in patients with

more severe symptoms. These data support the

hypothesis that some cases of ME/CFS may be

explained and potentially treated as a problem

with left ventricular function " (A Peckerman B

Natelson et al. FASEB 2003:17:5 Suppl: Part 2:

A853).

This study was summarised by Donna Krupa, APS

Newsroom, 10th April 2003: " Growing evidence

points to a possible problem with circulation.

Studies have found that ME/CFS patients may have

reduced blood flow in exercising muscles. A new

study provides indication of reduced cardiac function

in some patients with ME/CFS. It raises the

possibility that some ME/CFS patients may have

cardiac disorders that are subtle enough to escape

the current net of clinical cardiological diagnoses, but

may be significant enough in some patients to lead

to the clinical syndrome of ME/CFS " .

2003

" Cardiovascular reactivity is defined as the change on

blood pressure, heart rate, or other haemodynamic

parameters in response to physical or mental

stimuli. 13 variables showed significant

differences between ME/CFS patients and

controls. The degree of arterial stiffness of the large

arteries affects both the cardiovascular reactivity and

the pulse wave velocity. The FRAS (Fractal &

Recurrence Analysis-based Score) differs between the

groups of healthy persons, hypertensives, and

ME/CFS patients. The HIS (haemodynamic

instability score) distinguished ME/CFS from

healthy subjects with 97% sensitivity and 97%

specificity. Based on these data, it appears that the

HIS can provide objective criteria (in) the

assessment of ME/CFS " (JE Naschitz et al. Journal of

Human Hypertension 2003:17:111-118).

2003

" CFS is a clinically defined illness. Patients

frequently report an infection as a precipitating

event. Accumulating evidence points to a problem

with circulation in ME/CFS. Although

abnormalities in single systems may be insufficient

to cause a circulatory dysfunction, cumulatively

they could produce significant deficiencies in organ

blood flow and symptoms. Supporting this

possibility, a magnetic resonance spectroscopy study

indicated that patients with ME/CFS may have

reduced blood flow in exercising muscles, and

another study using nuclear magnetic imaging found

evidence of post-exercise reduction in brain blood

flow in ME/CFS.

Based on this evidence, we hypothesised that

patients with ME/CFS have reduced cardiac output.

This present study tested this hypothesis using

noninvasive impedence cardiography.

These results provide evidence of reduced cardiac

output in severe ME/CFS (and) there might be

periods in daily life when demands for blood flow

are not adequately met, compromising metabolic

processes in some vascular compartments. Some

percentage of patients (with) ME/CFS may in fact

have covert heart disease. The abnormalities

causing a reduction in cardiac output in ME/CFS

may be dispersed over multiples systems. Even

marginal reductions in cardiac output can result in

selective underperfusion during activities that

increase demand for blood flow. Inquiries should

be directed at conditions that may not be overtly

expressed in symptoms of ME/CFS, such as

underperfusion in the kidneys and the gut, as the

organs in which initial conservation of cardiac

output takes place " (A Peckerman, B Natelson et al.

Am J Med Sci 2003:326:2:55-60).

Media coverage of this important paper included the

following:

WebMD Medical News: 14th April 2003: " Many

people with ME/CFS may have a serious heart

problem. When you exercise, your heart pumps

out more blood. But these patients' hearts

actually pump less blood. 'Basically we are talking

about heart failure' Peckerman tells WebMD.

'ME/CFS is a progressive disease'. Emory

University cardiologist ph I III MD, says

Peckerman's findings are very interesting (and)

he agrees that these patients have serious heart

problems " .

2003

" ME/CFS is a debilitating condition of unknown

aetiology. Recent studies using brain spectroscopy

have revealed metabolic disturbances with

significantly elevated choline levels in various

regions of the central nervous system.

In addition, we have recently shown that

abnormalities specific to the cholinergic pathway

also exist in the peripheral microcirculation of

ME/CFS patients (and) our findings might have

important implications for vascular integrity in

ME/CFS. ME/CFS is commonly associated with

viral onset and immunological disturbance

sometimes linked to persistent viral infection. The

work described here provides new evidence of

disruption to ACh pathways specifically within the

peripheral circulation of ME/CFS patients " (F Khan,

V Spence et al. Clin Physiol Funct Imaging

2003:23:282-285).

2004

" Aberrations of cardiovascular reactivity (CVR),

an expression of autonomic function, occur in a

number of clinical conditions. Recently, a CVR

pattern particular to ME/CFS was observed.

Pathological disturbances may alter cardiovascular

reactivity. Our data support the existence of

disease-related CVR phenotypes. The importance of

recognising disease-specific CVR phenotypes may

(offer) supporting data for the diagnosis of certain

disorders. Recognising the ME/CFS reactivity

phenotype has been found useful in supporting the

clinical diagnosis of ME/CFS. Furthermore, CVR

phenotype may provide an objective criterion to

monitor the course of dysautonomia in ME/CFS "

(Naschitz JE et al. QJM 2004:97:3:141-151).

2004

" Research into ME/CFS is hindered by considerable

heterogeneity. There has been speculation that many

of the neurological symptoms might be

cholinergically mediated. As well as these

neurological findings, there has been a recent report

of autoantibodies specifically to muscarinic receptors

in many ME/CFS patients, suggesting that there

might be subgroups withion the ME/CFS construct

that are associated with autoimmune abnormalities

of cholinergic muscarinic receptors.

Apart from its neurotransmitter functions,

acetylcholine is a prominent vasodilator whose action

is dependent upon an intact layer of endothelial cells

that line the lumen of all blood vessels. In most

medical conditions associated with cardiovascular

disease there is a blunted response to acetylcholine.

However, we have reported increased responses to

acetylcholine in the cutaneous microcirculation of

ME/CFS patients. There was a significantly increased

response to substance P in ME/CFS patients and this

was often accompanied by a spreading flare and

localised oedema, a finding not observed in control

subjects. (This may be due to) a heightened

sensitivity to substance P in terms of its histamine

releasing properties. Indeed, sensitivity to

histamine has been implicated in ME/CFS

pathogenesis. The data demonstrated that the

dynamics of the acetylcholine-stimulated blood flow

response is significantly different in ME/CFS patients

compared with control subjects, possibly via a viral

mechanism.

(This) acetylcholine sensitivity is specific to a

sub-group of patients within the ME/CFS construct

(and) points to a problem on the vascular

endothelium of ME/CFS patients. We are confident

that the findings of increased sensitivity to

acetylcholine in ME/CFS patients are robust and

unusual. Our results are important in terms of

vascular control mechanisms in this patient group

and may be relevant to the problems of

orthostatic instability that is so evident in most

ME/CFS patients " (VA Spence et al. Prostaglandins,

Leukotrienes and Essential Fatty Acids

2004:70:403-407).

2004

" While the cause of ME/CFS remains to be

elucidated, extensive literature exists on the role

of a variety of infectious agents; up-regulation of

anti-viral pathways; immune abnormalities;

disruption to the hypothalamic-pituitary-adrenal

(HPA) axis; neuropsychological impairments;

dysfunction of the autonomic nervous system;

oxidative stress; and lipid peroxidation.

Looking at the literature as a whole, there are

various strands of evidence suggesting that the

vascular system in ME/CFS is compromised. Many

ME/CFS patients are unaware that something as

simple as being upright can trigger a cluster of

symptoms such as dizziness, altered vision, nausea,

fatigue, headache, sweating and pallor.

Orthostatic intolerance is characteristic of so many

of these ME/CFS patients that it could very well

serve as a definable subset. It has been

suggested by some that orthostatic intolerance in

ME/CFS is nothing more than deconditioning

associated with bed rest (but) vascular

dysfunction appears to be best supported by the

data.

Some subjects show autonomic dysfunction in their

internal organs vasculature (and) evidence points

towards enhanced pooling within the internal

organs and pelvic circulation. The onset of

orthostatic symptoms in many ME/CFS patients is

often predated by a viral infection. There is clearly a

problem with local vasodilator and vasoconstrictor

mechanisms in these patients. There is a significant

body of evidence pointing to vascular dysfunction

in the peripheral circulation of patients with

ME/CFS and this is in addition to blood flow

abnormalities within the central nervous system "

(V Spence & J . Biologist 2004:51:2:65-70).

2004

Lerner et al demonstrated abnormal cardiac wall

motion at rest and in cardiac biopsies: " A progressive

cardiomyopathy caused by incomplete virus

multiplication in ME/CFS patients is present " (Lerner

AM et al. In Vivo 2004:18:4:417-424).

2005

A study of adolescents with ME/CFS looked at blood

pressure, arterial stiffness and arterial wall

thickness. Arterial stiffness, expressed as common

carotid distension, was lower in adolescents with

ME/CFS, indicating stiffer arteries. " Pain perception

differed considerably between patients and controls

(and) this is the first study to confirm this

difference. The unexpected finding of stiffer arteries

in patients with ME/CFS warrants additional

investigation " (EM van de Putte et al. Paediatrics

2005:115:4:415-422).

2005

" Orthostatic intolerance certainly causes

breathlessness. The cause of the breathlessness is

probably a reduction in blood flow through the

heart and lungs. Patients with ME/CFS cannot

hold their breath as long as healthy people. This

was first noted by Dr Cheney " (DS Bell.

http://www.davidsbell.com/LynNewsV2N2.htm ).

2005

On 10th April 2005 Carol Sieverling posted on the

internet (Co-Cure) " The Heart of the Matter: CFS and

Cardiac Issues " – a 41 page exposition of Professor

Cheney's experience and expertise, from which

the following notes are taken and to both of whom

grateful acknowledgement is made.

Cheney's focus is based on the paper by Dr Ben

Natelson (clinical neurologist and Professor of

Neurology) and Dr Arnold Peckerman

(cardiopulmonary physiologist) at New Jersey Medical

Centre (ref: " Abnormal Impedance Cardiography

Predicts Symptom Severity in Chronic Fatigue

Syndrome " : Peckerman et al: The American Journal of

the Medical Sciences: 2003:326:(2):55-60).

This important paper says that, without

exception, every disabled CFIDS (i.e. ME

/CFS) patient is in heart failure.

There are two kinds of heart failure: one that any

cardiologist can diagnose in about a minute (which

ME/CFS patients do not have); the other is

Compensated Idiopathic Cardiomyopathy (CIM).

Given that at least 35% of those with CIM will die

within 5 years unless they receive a heart transplant,

but given that in 20 years' experience of ME/CFS

Cheney has never seen one patient go on to

transplant, why aren't those with ME/CFS-induced

CIM not dead? Cheney believes it's because ME/CFS

itself is protecting patients from a deeper problem

that is often missed because it is so well-hidden.

The problem

The New Jersey team looked at many things in

ME/CFS patients and they found something: a " Q "

problem. " Q " stands for cardiac output in litres per

minute. In ME/CFS patients, Q values correlated

-- with great precision – with the level of

disability. Q was measured using impedance

cardiography, a clinically validated and Government

agency-recognised algorithm that is not

experimental.

Normal people pump 7 litres per minute through

their heart, with very little variance, and when

they stand up, that output drops to 5 litres per

minute (a full 30% drop, but this is normal).

Those two litres are rapidly pooled in the lower

extremities and capacitance vessels. Normal people

do not sense that 30% drop in cardiac output when

they stand up because their blood pressure either

stays normal or rises -- the body will defend blood

pressure beyond anything else in order to keep the

pulse going. This is critical to understanding what

happens in ME/CFS patients.

However, what the New Jersey team found in

people with ME/CFS was astonishing –when

disabled ME/CFS patients stand up, they are on

the edge of organ failure due to extremely low

cardiac output as their Q drops to 3.7 litres per

minute (a 50% drop from the normal of 7 litres

per minute).

The disability level was exactly proportional to the

severity of their Q defect, without exception and

with scientific precision.

Symptoms

The New Jersey team then looked to see if there

were any symptoms that were observable in disabled

ME/CFS patients but not in others and they found

that there was only one such symptom that was

seen in patients with a Q problem: post-exertional

fatigue. To quote Cheney: " That is, when you push

yourself physically, you get worse " .

ME/CFS patients have a big Q problem; to quote

Cheney again: " all disabled ME/CFS patients, all of

whom have post-exertional fatigue, have low Q

and are in heart failure " .

Post-exertional fatigue (long documented as the

cardinal feature of ME/CFS but not of non-specific

states of chronic fatigue) is the one symptom that

correlates with Q. Among disabled ME/CFS

patients, 80% had muscle pain; 75% had joint

pain; 72% had memory and concentration

problems; 70% had unrefreshing sleep; 68% had

fever and chills; 62% had generalised weakness;

60% had headaches, but 100% had

post-exertional fatigue.

In Cheney's model, symptoms in ME/CFS reflect the

interaction between Q and how the body

compensates for too low a Q, so depending on the

nature of the compensation (which is individually

distinct), there is an array of symptoms that is

individually determined and which will arise out of

factors unique to each person.

Cheney posits that when faced with a low Q, the

body sacrifices tissue perfusion in order to

maintain blood pressure: ie. microcirculation to the

tissues of the body is sacrificed to maintain blood

pressure so that the person does not die in the face

of too a low Q. This compensation is what is going

on in the ME/CFS patient.

In the Peckerman study, the data on the disabled

ME/CFS patients reveals that even when they are

lying down, their Q is only 5 litres per minute (not 7

as in normals). When disabled ME/CFS patients

stand up, the Q of 5 litres per minute drops to 3.7

litres per minute, so these patients do not have

adequate Q to function. The lower the Q, the more

time the patient will spend lying down because lying

down is the only time they come close to having

sufficient cardiac output to survive.

Compensated Idiopathic Cardiomyopathy

Cheney states that it is important to note that the

body does not sacrifice tissue perfusion equally

across all organ systems: instead, it prioritises the

order of sacrifice and one can observe the

progression of ME/CFS by noting this

prioritisation.

Two organ systems in particular have a protective

mechanism (the Renin Angiotensin System, or RAS)

against restricted tissue perfusion: the lung and the

kidneys. These organs can sustain the greatest

degree of Q problems because of this extra

protection. Additionally, the heart and the brain also

have this extra protection, even in the face of an

extremely low Q. Therefore the lung, the brain, the

kidneys and the heart are a bit more protected than

the liver, the gut, the muscles and the skin from a

drop in Q.

In what order is tissue perfusion sacrificed, and

what are the consequences? Certainly, Cheney's

submission seems to tally with the experience of

long-term ME/CFS sufferers.

The first is the skin: if the microcirculation of the

skin is compromised, several problems can arise.

One is that without adequate microcirculation to the

skin, the body cannot thermoregulate anymore: the

patient cannot stand heat or cold and if the core

temperature rises, the patient will not be able to

sleep and the immune system will be activated. In

order to regulate that problem, the body will activate

thyroid regulation which will down-regulate in order

to keep the body temperature from going too high.

The result of this is that the patient develops

compensatory hypothyroidism, which means that now

the patient will have trouble with feeling cold. Also,

the body will not be able to eliminate VOCs (volatile

organic compounds), which are shed in the skin's oil

ducts, so VOCs build up in the body's fat stores and

the patient becomes progressively chemically

poisoned by whatever is present in the environment

-- in other words, the patient develops Multiple

Chemical Sensitivity (MCS).

The second effect: if things get worse, the next

microcirculation to be sacrificed is that to the

muscles and the patient will have exercise

intolerance and s/he cannot go upstairs. If things

get still worse, the patient begins to get fibromyalgic

pain in the muscles. Cheney posits that if

microcirculation to the joints becomes compromised,

it may precipitate pyrophosphoric acid and uric acid

crystals and the patient starts to have arthralgia

linked to this circulatory defect.

The next system to be compromised is the liver and

gut. One of the first things the patient may notice

in this stage of disease progression is that there

are fewer and fewer foods s/he will be able to

tolerate, partly because microcirculation is

necessary for proper digestion. Also the body will

not secrete digestive juices so whatever food is

tolerated will not be properly digested: if food

cannot be digested, there will be peptides that are

only partially digested and therefore are highly

immune-reactive; they will leak out of the gut into

the bloodstream, resulting in food allergies and /

or sensitivities.

The body will be unable to detoxify the gut ecology,

so the gut will begin to poison the patient, who will

feel a sense of toxic malaise, with diarrhoea,

constipation, flatulence and all kinds of gut

problems. If this gets worse, a malabsorption

syndrome will develop, resulting in increasing toxicity

in which the patient feels " yucky " and which can

manifest as a variety of skin disturbances (for

instance, a rash), as well as problems in the brain.

The fourth affected system is the brain: Cheney

posits that there is a devastating effect in the

brain as a result of liver / gut dysfunction, which

can quickly toxify the brain, resulting in

disturbances of memory and of processing speed.

Also, the hypothalamus begins to destabilise the

patient from the autonomic nervous system

perspective. In all probability, the brain and heart

suffer simultaneous compromise, but patients

usually notice the brain being affected much

earlier than the heart – this is because heart

muscle cells have the greatest mitochondrial

content of any tissue in the body, so when the

mitochondria are impaired, the heart muscle has

the greatest reserve. Even if the patient is

sedentary with not too much demand on the heart,

s/he can still think and make great demands on the

brain, and energy is energy, whether it is being used

physically or cognitively.

The fifth affected system is the heart: Cheney

posits that the effect of compromised

microcirculation upon the heart has an " a " part and a

" b " part: part " a " is the manifestation of

microcirculation impairment and part " b " is " the

event horizon " .

Part " a " : manfestation of microcirculation

impairment: the initial manifestation of

microcirculatory impairment of the heart is

arrhythmia with exercise intolerance: when the

patient goes upstairs, more cardiac output is

needed but the patient cannot sustain it. As it gets

worse, there will be mitral valve prolapse (MVP)

because of inadequate capillary function. Finally,

when there are even more severe

microcirculatory problems, the patient starts to

get chest pain as the myocardial cells die because

they cannot get adequate oxygen.

Part " b " : the event horizon: (once this line is passed,

there is no going back): Cheney's view is that the

" event horizon " with respect to the heart is this:

when the microcirculation defect within the heart

itself begins to impact Q itself, a vicious circle

begins – microcirculation impairment reduces the Q,

which produces more microcirculation impairment,

which produces even more Q problems, so down

goes the patient into the next phase of cardiac

failure, which is the lung.

The sixth affected system is the lung and kidney:

cardiac failure in the lung produces congestive

heart failure (CHF) and pulmonary oedema, then

the kidney is affected (the kidney is the last to go

because it has the RAS back-up system).

Combined with liver impairment, this stage is

known as hepatorenal failure, which is the

requisite cause of death due to Compensated

Idiopathic Cardiomyopathy.

For some reason, there is something about ME/CFS

that keeps patients from progressing across the final

event horizon, although Peckerman believes that a

certain percentage of CFIDS patients are heading

that way. How will a patient know if s/he

eventually loses the ability to compensate? They

will know it if when they lie down, they are short

of breath.

The cause of the cardiac output problem

Cheney's view is that the cardiac muscle has lost

power because the mitochondria are dysfunctional

due to a redox-state problem. Redox is a reversible

chemical reaction in which one reaction is an

oxidation and the reverse is a reduction.

What causes the redox-state problem? Cheney does

not know, but he does know that in ME/CFS, like MCS

and Gulf War Syndrome, there is a redox-state

problem. There is, however, something unique in

ME/CFS, which is that the redox-state problem seems

centred on the heart. In Cheney's model, candidates

include viruses in an interaction with toxins.

Cheney comments on Professor Pall's work on

the role of peroxynitrite in ME/CFS. Uric acid is a

powerful scavenger of peroxynitrite, as is uric acid.

Cheney has measured uric acid levels in ME/CFS

patients and has found them to be amongst the

lowest levels he has ever measured in his entire

medical career.

Cheney notes that Dr Les Simpson in New Zealand

found that the red blood cells of patients with

ME/CFS were deformed and when deformed, they

cannot get through the capillary bed and so cause

pain. An indication of such deformity is a drop in the

sedimentation rate (SED, or ESR) and Cheney has

observed that when measured in a laboratory,

ME/CFS patients' sedimentation rate is the lowest

he has ever recorded, which confirms to Cheney

that ME/CFS patients have an induced

haemoglobinopathy. He believes that the ME/CFS

patients with the lowest sedimentation rate may

have the greatest degree of pain.

The more deformed the red blood cells, the more

pain may be experienced. Some ME/CFS patients

have a problem similar to that of sickle cell

anaemia in this regard, and sickle cell patients

have unbelievable pain. Cheney emphasises that it

is bad enough when patients do not perfuse their

muscles and joints (because of poor microcirculation)

but it is even worse when red blood cells are so

deformed that they can barely get through the

capillaries or are blocked entirely.

Cheney notes that in the Laboratory Textbook of

Medicine, there are only three diseases that lower

the sedimentation rate to that level: one is sickle

cell anaemia (a genetic haemoglobinopathy); the

second is ME/CFS (an acquired haemoglobinopathy)

and the third is idiopathic cardiomyopathy.

Cheney observes that in order to improve cardiac

output in ME/CFS, patients need to lie down, as this

increases the cardiac output by 2 litres per minute.

He notes that some ME/CFS patients need to lie

down all the time to augment their blood volume in

order to survive. He has found increasing the intake

of potassium to be helpful (potassium induces

aldosterone, a hormone that significantly increases

blood volume), and that magnesium is beneficial as

it is a vasodilator and helps reduce the resistance

the blood encounters.

Cheney is at pains to emphasise that none of these

measures is a cure ---they are simply means to help

patients disabled with ME/CFS remain as functional

as possible.

Cheney's credentials include more than two decades'

experience treating over 5,000 ME/CFS patients in 15

countries; research positions relevant to ME/CFS with

the US Centres for Disease Control; Emory University

and the University of Pennsylvania, and numerous

journal articles. He was a founding director of the

International Association of Chronic Fatigue

Syndrome, an association of scientists and clinicians.

2005

" There is mounting evidence that oxidative stress

and lipid peroxidation contribute to the disease

process and to some of the symptoms (in

ME/CFS). While free radicals may generate tissue

injury, it is also evident that other oxidative

by-products, especially isoprostanes, can exert

potent biological activity and act as a powerful

vasoconstrictor of the peripheral vasculature.

Such biological effects may be instrumental in the

development of some of the vascular features that

characterise patients with ME/CFS. The novel

findings of this study are that patients with

ME/CFS have significantly elevated levels of

F2-isoprostanes alongside other key markers of

oxidative stress, and that these correlate with

various ME/CFS symptoms.

This is the first time that elevated levels of

isoprostanes have been reported in patients with

ME/CFS. Isoprostanes have potent biological effects

associated with increased cell permeability. They

have also been shown to be powerfully

vasoconstricting and are involved in endothelial

injury.

Exercising muscle is a prime contender for

excessive free radical generation, with recent

evidence pointing to good correlations between

muscle pain thresholds and fatigue with various

blood markers of oxidative injury in ME/CFS

patients, and further evidence of viral persistence

in muscle tissue in some patients with the illness.

Research evidence has demonstrated that

incremental exercise challenge potentiates a

prolonged and accentuated oxidative stress that

might well account for post-exercise symptoms in

ME/CFS patients.

It could be suggested that ME/CFS is an

inflammatory condition with many patients in a

pro-oxidant states, and this could explain many of

the pathological manifestations that underlie the

illness " (G Kennedy, VA Spence et al. Free Radical

Biology & Medicine 2005:39:584-589).

2005

Researchers at the US centres for Disease Control

(CDC) reported that patients with ME/CFS exhibited

scores on assessment tools that quantify impairment

and symptoms occurrence, duration and severity and

were able to be identified with precision. The

authors reported that the ME/CFS patient

exhibited scores similar to patients with

congestive heart failure (WC Reeves et al. BioMed

Central Medicine, 15th December 2005).

2006

Researchers used serial cardiopulmonary exercise

tests to support a diagnosis of ME/CFS. The authors

noted: " In the absence of a second exercise test, the

lack of any significant differences would appear to

suggest no functional impairment in ME/CFS

patients. However, the results from the second test

indicate the presence of an ME/CFS related

post-exertional malaise. It might be concluded that

a single exercise test is insufficient to demonstrate

functional impairment in ME/CFS patients. A second

test may be necessary to document the atypical

recovery response and protected malaise unique to

ME/CFS " (VanNess MJ et al. Medicine & Science in

Sports & Exercise 2006:38:5: Suppl: S85).

2006

In his September 2006 seminar (available on a

two-DVD boxed set from videos@... ),

Professor Cheney again warned that aerobic

exercise may kill the patient with ME/CFS. As before,

Cheney acknowledges his debt to the work of

Peckerman. Cheney noted that there is an objective

database in key medical literature that includes

evidence of diastolic dysfunction and heart failure in

ME/CFS.

There are two types of heart failure: systolic (which

is a failure to eject) and diastolic (which is not a

failure to eject, but a failure to fill properly).

Diastolic heart failure was first described in the

1980s but there was no significant literature until

the 1990s, and no significant way to measure it until

2001.

Whilst there has been little recognition of the

existence of diastolic dysfunction by some

cardiologists (considered a relative rarity in 1986), in

2006 an article entitled " Diastolic heart failure – a

common and lethal condition by any name " was

published by Gerard Aurigemma, who concluded

that:

" the development of specific, effective management

approaches for diastolic heart failure must become a

high priority " (NEJM 2006:355:3:308-310). The NEJM

carried a significant paper on more than 4,500

patients studied with diastolic heart failure; this

increase is unexplained, but is accelerating, and

Cheney wonders if it is in fact an explosion of

ME/CFS.

A simplistic summary of Cheney's seminar is as

follows:

The evolution of ME/CFS

There are four phases:

1. the onset, or trigger phase

2. the triad phase

3. the dynamic dysfunction phase (although the

fatigue and pain and brain dysfunction are a little

better, patients in this phase can do less than

when they were more sick)

4. DNA phenotype adaptation phase (there is a

phenotypic adaptation that locks this in at gene

level)

Key scientific articles

Phase 1: (immune activation: fever, swollen glands,

sore throat, malaise: general indications of immune

activation)

* Suhadolnick et al (Temple University, USA)

* Komaroff et al (Harvard, USA)

* Klimas et al (Miami, USA)

Phase 2: (the centre of gravity of this illness:

fatigue, brain problems and pain; xenobiotic toxicity

coming from the gut and the environment)

* McGregor et al (Newcastle University, Australia)

* Pimental (UCLA, USA)

Phase 3: (the brain and heart components)

* Demitrack et al (NIH, USA)

* Moorkens et al (Antwerp, Belgium)

* Schwartz et al (Harvard, USA)

* Peckerman et al (NMJ & D, USA)

* Drexler et al (Hanover, Germany)

Phase 4: (phenotypic and genotypic adapatation -->

oxidative stress)

* Vernon et al (CDC, USA)

* Kerr et al (London, UK)

* Urowitz et al (Berkeley, USA)

* Pall (WSU, USA)

* Kennedy et al (Cheney's overhead stated " USA " ,

but if he means Kennedy and Spence, it should

be Dundee, Scotland)

Oxidative stress links ME/CFS to fibromyalgia,

multiple chemical sensitivity and Gulf War Syndrome.

Do people recover from (ME)CFS?

Functional recovery is seen: one's ability to do things

can improve, but it can go the other way, or there

may be no change over time. Komaroff's data from

Harvard is that after 10 years of illness, there is only

a 30% chance of any functional recovery.

The Physical Examination

In phase 1: (immune activation) one sees

* lymphyodynia (seen in 80-90%)

* crimson crescents bilaterally on soft palate (seen

in 80%)

* sub-normal temperature

In phase 2: one sees

* evidence of subcortical brain injury

* vestibular dysfunction (seen in 94%)

* hyper-reflexia, especially of the knees

and ankles (seen in 70%)

In phases 3 and 4: the most interesting are the

metabolic disturbances:

* there is shortened breath-holding capacity (seen

in 60%)

* there is very poor oxygen transport (seen in

90%): pulse oximetry readings measuring

saturation of haemoglobin show a significant

inhibition to desaturate

* there is finger-print destruction (seen in 50%):

cross-hatching occurs, with degradation of the

ridges; punch biopsies found perivascular

lymphoid infiltrates ie. an inflammatory cuffing

exactly as seen in lupus, which signifies a

non-specific immune activation issue (so the

finger-print changes could be reflecting much

more than just loss of finger-prints and may

represent a vasculopathy)

* there is sub-normal temperature (seen in 80%)

there is low systolic blood pressure (in 50% of

patients it is less than 100mmHg)

there is orthostatic B/P or pulse changes (seen in

70%)

These findings portend significant physiological

issues, chief of which is that oxygen is being

prevented from getting into the cell, and if there is

no oxygen, there is no energy.

Magnetic Resonance Spectroscopy

* 70% of patients show elevated lactate levels in

the ventricular system (the lactate elevation is

not normal and indicates a defect in energy in

the brain: ME/CFS patients have significantly

elevated lactate levels and the fatigue correlated

significantly with the level of lactate)

* 10% have evidence of neuronal destruction and

elevated choline peaks, typically in the

perivascular areas

Magnetic Resonance Imaging

* 78% of patients have punctate lesions which are

most consistent with small strokes and there is

evidence to support this

Mixed venous blood gas picture

* PvO2 is 25 (it should be 40)

* PvCO2 is 55 (it should be 45)

This is a differential hypoxia with hypercarbia. There

are only two diseases where this is seen: one is

pulmonary hypertension; the other is ME/CFS.

Where does the oxygen go? It's being transported

somewhere, but not to the mitochondria. ME/CFS

patients have been shown to have increased pooling

of extra-cellular fluid in the belly, pelvis and legs

which might contain this dissolved oxygen, but it is

more likely being consumed by the oxidative pathway

to create superoxide in massive amounts.

Superoxide is the progenitor of all free radicals. The

consequences are increased intra-cellular oxdidative

stress.

ME/CFS as cellular metabolic dysfunction

There are problems at cell level in energy production,

and because of this degraded energy problem,

patients suffer a defect in the ability to detoxify

toxins, especially in the portal circulation (giving rise

to gut toxicity as seen in phase 2). Gene alterations

(seen in phase 4) generate a massive disturbance in

the development of energy at the cell level. If you

lose energy, you lose glutathione, but the more

glutathione you give, the more you just create

oxidised glutathione, which generates loss of citrate,

causing a left shift on oxyhaemoglobin desaturation.

Citrate also binds to magnesium, so over time the

patient will develop a severe magnesium depletion

syndrome. When that happens, you've had your last

good night's sleep: when you lose magnesium, you

can't sleep any more.

In ME/CFS, these serious issues are a big problem,

especially in the brain, the heart and in muscle.

ME/CFS is a compensatory response to down-regulate

energy production and oxygen transport in order to

reduce tissue damage.

Attempts to push beyond energy limits will

cause injury.

Prolonged energy deficits can cause semi-permanent

DNA phenotype adaptations and complications can

occur, especially within energy-sensitive systems

such as the heart, the brain and the muscles.

In ME/CFS, catalase is deficient in the heart, lungs

and liver (catalase is the most protective enzyme in

the body against the ravages of superoxide), and

Cheney noted that electromagnetic fields [EMFs]

" screw up " superoxide dismutase (SOD), which is a

major anti-oxidant scavenger.

Is there an ME/CFS-associated cardiomyopathy?

According to Cheney, a subset of " CFS " patients

suffers from diastolic dysfunction.

Cheney reports that echocardiograms (sonograms of

the heart) indicate that as many as 99% of his

ME/CFS patients test positive for some level of

diastolic dysfunction.

ME/CFS patients have a high heart rate but a low

cardiac output. In ME/CFS there is a cardiac

dimension that is independent of (but not excluding)

autonomic function or blood volume.

82% of patients have abnormal cardiac impedence.

Cheney says that at least half of patients exhibited

atrial cavitation, and that when these patients stood

up, in 80% the filling volume collapsed. He tested

this with magnesium and the results were

significant: magnesium restored 12% of energy in

one minute. Magnesium affects the intracellular

energetics, proving that patients have a

" tremendous " energy problem that is very sensitive

to magnesium. (The reason magnesium is so

important is that without it, ATP cannot be converted

to ADP for the production of energy).

Cheney says that ME/CFS patients " squeeze the hell "

out of their left ventricle, resulting in a " whopping "

70% increase in left ventricular wall motion

thickness. The reason why patients are squeezing

so hard is because they do not have enough energy

to fill the chambers of the heart properly so they are

trying to compensate by squeezing a lot harder (ie.

the way patients are compensating for this loss of

cardiac output is by squeezing the left ventricle much

harder).

There are significant consequences of this. One

consequence is that ME/CFS patients become

asynchronised (i.e. the heart can be filling and

ejecting at the same time).

If out of synchrony, the ventricle cannot cope, so

cardiac output is severely degraded.

A second consequence is that patients develop a

strain pattern, which is an indication of ischaemia.

Cheney has seen ischaemic changes in the inner

ventricular wall because of the increased squeezing.

Cheney has demonstrated that, because of the

increased left ventricular strain, the communication

between the right and left sides of the heart that

closed at birth (the foramen ovale) opens up and

becomes patent (Patent Foramen Ovale / PFO). This

hole in the heart produces a right to left shunt of

unoxygenated blood full of carbon dioxide as well as

products of liver metabolism – the liver is literally

draining into the right heart and the blood is being

shot straight to the brain. This was demonstrated

on the DVD by means of Trans Cranial Doppler

bubbles. It results in significant oxygen toxicity.

It is increasingly clear that in ME/CFS, a diminished

threshold for oxygen toxicity exists, and that each

patient will have a unique threshold. These findings

have a significant negative effect on Accident &

Emergency and operating theatre uses of oxygen

during surgery, because an ME/CFS patient could be

given too much oxygen and be killed on the

operating table.

The complications of PFO include:

* cerebral aneurysm

* multiple mini-strokes

* cerebral hypoperfusion produces pressure

headaches, migraine, cognitive impairment and

a lower seizure threshold

* venous hypoxia complications are fundamentally

linked to intracellular acidosis which depletes

electron buffers

* depleted acid buffers leads to increased

sensitivity to diet, drugs and the environment.

PFOs cause significant instability.

There is a difference between diastolic dysfunction

and diastolic failure: in diastolic dysfunction there is

a filling problem but the body is compensating for it

and achieving enough cardiac output to match

metabolic demand.

Diastolic failure begins when the body can no

longer compensate and there is a reduction in

cardiac output. Cheney repeated that this is seen

in 80% of ME/CFS patients.

If patients draw down their lifestyle to live within

the means of the reduced cardiac output, then

progression into congestive cardiac failure (CCF) is

slowed down, but if things continue to progress, a

point will be reached where there is no adequate

cardiac output, and dyspnoea will develop, with

ankle oedema and other signs of congestive cardiac

failure.

The message from Cheney is clear: in order to

stay relatively stable, it is essential for the ME/CFS

patient not to create metabolic demand that the

low cardiac output cannot match.

According to Cheney, it is difficult to talk about a low

cardiac output without talking about the involvement

of the brain and the adrenal glands.

If the cardiac output goes down, in order not to die,

there is a rise in noradrenergic tone (also involving

the adrenal glands) to bring the output back up. In

ME/CFS, this is a serious problem, because when the

adrenals are exhausted, there will be low cardiac

output.

There is no such thing as an ME/CFS patient who is

NOT hypothyroid: this has nothing to do with thyroid

failure, but everything to do with matching metabolic

demand and cardiac output.

A mismatch between metabolic demand

and cardiac output, even very briefly, will

kill.

A major cause of death in ME/CFS is heart

failure.

2007

The 8th International Association of Chronic Fatigue

Syndrome (IACFS) Conference was held at Fort

Lauderdale, Florida, from 10th-14th January 2007.

The following extracts are taken from " Facts from

Florida "

http://www.meactionuk.org.uk/Facts_from_Florida.htm

* The conference was attended by over

250 clinicians and researchers from 28

different countries and there was a strong

sense that they were all co-operating to

build on the science. It is the science that

has freed the world from any doubt that

ME/CFS is a legitimate disease with an

aetiology that is not rooted in the psyche

-- Japanese and Swedish research teams

collaborated in a comprehensive study of

a neuro-molecular mechanism and

concluded that ME/CFS is an organic

disorder. It was described as " this

miserable illness " .

* The latest figures (January 2007) on the

economic impact of ME/CFS in the US are

between $22 billion and $28.6 billion

annually; in Japan, the figure is over $10

billion annually. The Japanese Government

recognises ME/CFS as a real threat not only

medically but also economically and has

initiated a large research programme into

causation and treatment.

* One of the most striking elements

was the convergence of research

findings: the three areas that came up

again and again were inflammation,

mitochondrial abnormalities, and vascular

problems.

* Three separate research teams found

evidence of microvascular problems in

ME/CFS.

* The significant confluence of findings

on elastase (a protease enzyme, i.e. it

digests and degrades a number of

proteins, including elastin, a substance

that supports the structural framework

of the lungs and other organs); vascular

problems; apoptosis (programmed cell

death); free radical production (highly

damaging to DNA, to cell membranes and

to proteins) and inflammation was

undeniable.

* Research findings addressed many

areas and provided yet more evidence that

cognitive processing differs in ME/CFS

compared with controls; there is evidence

of distinctive chemical and molecular

differences in ME/CFS patients; there is

evidence of the role of specific viral

agents, and there is confirmation that

differences in gene expression exist

between ME/CFS patients and healthy

controls, as well as between subgroups

of " CFS " .

* The importance of sub-typing was

recognised and emphasised.

* Dr Ellie Stein from Alberta, Canada,

pointed out that suicide is the third leading

cause of death in ME/CFS (the others being

cancer and heart disease).

* In ME/CFS, testing for elastase,

RNase-L, C-reactive protein, selected

cytokines and NK cell activity are

recommended because they are objective

markers of pathophysiology and severity. In

addition, an exercise test/re-test of

cardiopulmonary function is necessary

because it is 100% objective and

confirms reduced functional capacity as

well as post-exertional malaise for

disability purposes. Further, lipid

abnormalities and evidence of metabolic

syndrome should be looked for.

Cardiovascular system

* Researchers are developing methods to measure

cardiovascular and cardiopulmonary health in ME/CFS

patients, which relates to oxygen consumption.

* ME/CFS patients' ability to work is impaired, as

shown by an abnormal exercise stress test. Margaret

Ciccolella and Snell et al from Stockton,

CA, demonstrated that patients show extreme

abnormalities in a next-day/second session of

exercise. They do not recover in 24 hours. In one

study, only one patient had recovered to baseline

within 48 hours. These changes in serial testing

point to a significant and confirmable physical

abnormality, verifying the cardinal symptom of

post-exertional malaise. This test/retest exercise

test is 100% objective and can prove to the

disability companies that ME/CFS is neither

malingering nor faking. In ME/CFS patients, the

measurements declined by about 25%, far more

than in other significant diseases such as COPD

and even heart failure.

* Post-exertional malaise following exercise

challenge results in fatigue, light-headedness,

vertigo, joint pain, muscle pain, cognitive

dysfunction, headache, nausea, trembling,

instability, and sore glands.

* In ME/CFS patients, there is cellular hypoxia —

oxygen is delivered to the cells of the heart, brain,

skeletal muscle and other organs, but the process

of turning oxygen into energy is derailed.

* Graded exercise therapy is ill-advised — if a

patient has abnormal oxygen consumption,

muscles will not have enough oxygen and exercise

will result in relapse.

* A US NIH-funded trial by Professor Barry Hurwitz,

a colleague of Professor Klimas at the

University of Miami, found that 70% of ME/CFS

patients have a low red blood cell volume.

Treatment to increase blood volume was

ineffective in respect of exercise tolerance and

fatigue.

* One of the highlights of the conference was the

presentation of Dr Vance Spence's work (University of

Dundee) on inflammation and arterial stiffness in

patients with ME/CFS – arterial stiffness is rarely

found in adolescents, but in ME/CFS these young

patients had higher levels of arterial stiffness than

diabetic patients. This work looked at

inflammatory factors (free radical by-products

and C-reactive protein, an inflammatory marker)

and found abnormally high levels of free radical

by-products and C-reactive protein in patients but

not in controls. C-reactive protein levels were

significantly correlated with increased arterial

stiffness.

A likely cause is elastase. Elastase is a central factor

in Professor Kenny de Meirleir's RNase-L paradigm

(see below), and Dr Baraniuk's cerebrospinal fluid

proteome study suggests elastase is implicated in

blood vessel problems in the brain of ME/CFS

patients. The logical consequences of increased

arterial stiffness are exercise intolerance and

diastolic (cardiac) dysfunction. The circulatory

problems seen in ME/CFS may originate in

endothelial cells lining all blood vessels. These cells

are involved not only in opening and closing blood

vessels but in the immune response as well, and

they are often attacked by pathogens.

* Professor Cheney presented evidence of

diastolic (cardiac) dysfunction in ME/CFS, with

evidence of another cardiac abnormality (patent

foramen ovale, or PFO). This results in hypoxia (low

oxygen levels relative to metabolic needs).

* Cheney stated that the cardiac index of

ME/CFS patients is so severe that it falls between

the value of patients with myocardial infarction

(heart attack) and those in shock.

* Professor Mark van Ness from the University of

the Pacific found that maximum aerobic capacity

(VO2 peak) is reduced in ME/CFS compared with

sedentary controls.

* Van Ness found that oxygen capacity at the

anaerobic threshold is reduced in ME/CFS.

* Van Ness also found that serum lactate is

elevated, suggesting an abnormally early shift to

anaerobic metabolism.

* In a subset of patients, Lerner (Wayne

State University, Detroit) described persistent EBV

and/or CMV in ME/CFS patients: in addition to having

high titres, all 37 patients studied had an elevated

heart rate at rest, recurrent T-wave inversion on

Holter monitoring, cardiac abnormalities and/or

biopsy-proven cardiomyopathy. Symptoms included

not only tachycardia but chest pain and syncope.

* According to Lerner, all ME/CFS patients have

abnormal T waves; inversion is seen in 96%; there

is resting tachycardia. Cardiac biopsies show

fibrosis, myofibre disarray and fatty infiltrates.

Other key areas of ME/CFS research reported in

" Facts from Florida " include Nuclear Medicine

(showing some of the abnormalities in functioning

that patients with ME/CFS experience on a daily

basis); Proteomics (the study of proteins made in

the cell, including evidence of unique markers in the

cerebrospinal fluid of ME/CFS patients that are

completely absent in controls and which were

described as " unbelievable " );

Virology (showing evidence of viral persistence in

ME/CFS patients); Gastrointestinal dysfunction

(evidence was presented of enterovirus in stomach

biopsies of 80% of ME/CFS patients, compared with

none in controls); Sleep disruption (due to a lack of

parasympathetic activity during attempted sleep

periods); Pain (described as a major feature in many

aspects of ME/CFS); Cognitive impairment (evidence

was presented suggesting that the central nervous

system correlates of cognitive dysfunction in ME/CFS

have an inflammatory basis); Immunology (evidence

of activated CD8 cells; poorly functioning NK cells;

novel findings – seen only in ME/CFS – of

abnormalities of the 2-5A pathway [RNase-L ratio];

cytokine abnormalities [pro-inflammatory

dysregulation]; increased TGF, and 27 times more

circulating immune complexes than in controls;

Neuroendocrine dysfunction (evidence of

neurobiological distinctions between 'pure' ME/CFS

and CFS/ME with psychiatric morbidity -- further

evidence that ME/CFS is not psychiatric in origin);

Genomics (the study of the function and interactions

of genetic material, including interactions with

environmental factors which play a significant role in

ME/CFS) and Paediatrics (with the presentation of

new paediatric diagnostic criteria from Professor

Leonard et al, which means there is now a

science-based instrument to correctly diagnose

children and adolescents with ME/CFS).

In summary, this international conference

demonstrated the difference between

science and psychiatry.

All the above evidence was available to the GDG but

they were directed not to consider it (J Inf

2007:55:6:569-571) and instead chose to refer to

" perceived exertion " , even stipulating that: " signs

and symptoms of cardiorespiratory disease should

not be attributed to CFS/ME " (52 page version,

15:1.2.1.4).

Evidence of cardiovascular

dysfunction continues to mount

Following publication of the Guideline, papers which

confirm and add to the existing body of knowledge

about cardiovascular dysfunction in ME/CFS continue

to be published. For example:

* a team from the US CDC produced evidence of

higher heart rate and reduced heart rate variability

during sleep in ME/CFS (Autonomic Neuroscience,

2007)

* a Belgian team published evidence of a genuine

intracellular inflammatory response in the white

blood cells in ME/CFS patients (Neuro Endocrinol

Lett, 2007)

* a Norwegian team demonstrated that adolescents

with ME/CFS have a sympathetic predominance of

cardiovascular regulation with hypovolaemia and

abnormalities of the reflex mechanisms during even

very mild orthostatic stress (Clin Physiol Funct

Imaging, 2007)

* a Japanese team published evidence from

echocardiographic examination demonstrating

significant differences in ME/CFS patients and

controls --smaller values of both left ventricular

end-diastolic dimensions and end-systolic, as well as

stroke volume and cardiac indices, with evidence that

a considerable number of ME/CFS patients have a

small heart compared with controls (Clin Cardiol

2008)

* a ish team noted that as long ago as 1997,

markers of inflammation were demonstrated in some

patients with ME/CFS, and that in 2005, vascular

stiffness was shown to have an impact on resting

and exercise-induced haemodynamics; aware of the

accumulating evidence that the cardiovascular

system is compromised in many patients with

ME/CFS, this team investigated the relationship

between inflammation and arterial stiffness in

ME/CFS patients. (If arteries become stiff, the heart

has to work harder and, ultimately, blood pressure

becomes higher.

Stiff arteries have been linked to kidney problems

and heart disease, and may contribute to the

orthostatic problems (dizziness on standing)

experienced by some ME/CFS patients).

This study demonstrated that the augmentation

index (a measure of arterial stiffness) was

significantly greater in patients with ME/CFS than in

controls and concluded: " The results of this study

have shown that patients with ME/CFS have high

serum CRP levels (C-reactive protein, a sensitive

biochemical marker of inflammation) indicative of

chronic inflammation. The combination of increased

arterial wave reflection, inflammation and oxidative

stress may result in unfavourable haemodynamics

and an increased risk of a future cardiovascular

event in these patients " (VA Spence et al. Clinical

Science 2008:114:561-566).

Undue influence of the Wessely

School on the NICE Guideline

The GDG claims that the Guideline " offers best

practice advice on the care of people with CFS/ME "

(52 page version, page 6) and that it is

" evidence-based " , even though little of it actually is

evidence-based, because (i) many of the RCTs on

which the GDG relies for its management

recommendations specifically exclude those with

ME/CFS, and (ii) the GDG was directed to disregard

the existing international evidence-base, focusing

only on the Wessely School model of " CFS/ME " .

Pertinent questions require urgent answers, for

example:

* are the Wessely School psychiatrists who advised

NICE via the Systematic Review team at the Centre

for Reviews and Dissemination at York (and as

Stakeholders) all still convinced that the exercise

regimes to be meted out by the " CFS " Centres on the

recommendation of the NICE Guideline pose no harm

for those with ME/CFS?

* is Professor Pinching (who, it has been

confirmed by NICE, was instrumental in formulating

the GDG's remit and who is very supportive of the

Wessely School's behavioural model of " CFS/ME " , as

confirmed in a personal communication of 17th May

2001) also certain that incremental aerobic exercise

is safe for every ME/CFS patient as recommended in

the Guideline?

* are the peer reviewers at the MRC who approved

the PACE trial protocol still certain that the

incremental exercise component poses no harm for

people with ME/CFS?

* have all MRC trial participants been screened for

cardiac anomalies before starting the trial, or are the

Principal Investigators (psychiatrists White and

Sharpe, assisted by Simon Wessely) content

to rely on the certainty that they themselves can

never be held accountable for any harm to any

patient, since all participants must sign a compulsory

waiver, which means that no participant can ever

pursue any claim for medical negligence or damages?

Problems with delivery of the

NICE Guideline's recommendations

The NICE Guideline states that participation in

graded exercise should be a co-operation between

the therapist and the patient, but in practice the

evidence is that this simply does not happen.

Apart from the concern recorded in the Gibson Inquiry

Report of 2006 about his commercial conflicts of

interests arising from his involvement with and his

work for the medical insurance industry

(http://www.erythos.com/gibsonenquiry/Docs/ME_Inquiry_Report.pdf),

there are other equally disturbing matters that seem

to involve psychiatrist Professor White.

It is a matter of record that the Royal Free

(Hampstead) NHS Trust Fatigue Service – a very

large Centre -- was coercing " CFS/ME " patients into

signing up to participate in CBT and graded exercise

on pain of being refused access to a physician unless

they agreed to do so (i.e. it was being made clear

to patients that they would have access to a

physician for medical advice at the Centre only if

they agreed to participate in CBT and graded

exercise therapy regimes; if patients declined to

enter into a contract to participate in such regimes,

they would be discharged and would have no access

to a physician at the Centre).

In the absence of the part-time Clinical Lead at the

Royal Free Fatigue Services Centre, Dr le

, the person in overall charge is Professor

White.

It is understood that Professor White has been

recruiting patients attending the Royal Free Fatigue

Services Centre to the MRC " CFS/ME " trials (of which

he is a Principal Investigator), which raises the

possibility that he is recruiting only

CBT/GET-compliant patients to his trials, which

would decrease the number of trial drop-outs at a

stroke. Staff at the Royal Free Fatigue Services

Centre ( and Levy, a graded

exercise therapist and an occupational therapist

respectively) are team members on the MRC PACE

trial.

Written evidence exists that, less than one month

after publication of the NICE Guideline on " CFS/ME "

on 22nd August 2007, the Royal Free Fatigue

Services Centre policy (that patients believed denied

them access to a physician unless they agreed to

take part in a regime that is already known to be

harmful in 50% of participants) would seem to have

been in breach of the assurances contained in the

Guideline.

The NICE Guideline is unambiguous and states in ten

places that if a CFS/ME patient refuses CBT and GET,

such refusal should not end the treatment contract

with the doctor and it stipulates that patients may

not be discharged from medical care -- see the Full

Guideline, pp 28, 31, 116, 130, 158, 178, 214, 259,

283 and 298. For example, page 28 of the Guideline

states: " Healthcare professionals should be aware

that – like all people receiving care in the NHS --

people with CFS/ME have the right to refuse or

withdraw from any component of their care plan

without this affecting other aspects of their care, or

future choices about care " . The Guideline is clear

that a patient's right to care should not be limited by

the personal treatment preferences of an NHS

professional: " Personal views or beliefs are not

allowed to impede any individual's access to care

and support " (page 186). Further, on page 213, the

Guideline states: " The person with CFS/ME and

healthcare professionals involved in their care will

make decisions in partnership " .

It has been reported both by patients and by medical

consultants that this fundamental principle,

enshrined in law and endorsed by NICE, has being

actively negated, in letter and in spirit, by NHS

practitioners at a leading London CFS/ME Centre

http://www.meactionuk.org.uk/COERCION_AS_CURE.htm

The NICE Guideline states: " Objectives of the CBT

programme must be agreed with the patient, and

they must clearly be willing to take part " . Indeed

so, but some Centres have a way of inducing

" consent " , and patients who hesitated were

threatened with having no access at all to a

physician (which, apart from any symptomatic

medical care, they need in order to support their

claim for state benefits).

It has also been established that this same Centre is

no longer prepared to support individual patients'

applications for Disabled Living Allowance but simply

hands patients a pro-forma letter.

This is in clear breach of the Guideline, which states

that every person with " CFS/ME " should be offered

assistance with negotiating the healthcare, benefits

and social care systems (52-page version, section

1.1.3.2).

In his Editorial in the BMJ in which he zealously

supported the NICE Guideline's recommendation for

" CFS/ME " to be managed by the behaviour-modifying

interventions of CBT and graded exercise (BMJ 1st

September 2007:335:411-412), White asserted: " We

remain unsure how to classify (CFS/ME) " .

This is in total disregard of the WHO classification of

almost 40 years -- an era, as noted in an eBMJ Rapid

Response to that Editorial, when great care was

taken over detail and documentation in the

identification of a disease entity.

Professor White is unremitting in his promotion of

the NICE Guideline. On 23rd July 2008 he wrote in

the eBMJ: " Both patients and their family physicians

seemed to share uncertainty about either whether

CFS existed or how to treat it. Physicians'

uncertainty and ignorance cannot be attributed to a

lack of available guidance. Fortunately the UK has

seen a recent publication of the most authoritative

guideline so far; that produced by the National

Institute for Health and Clinical Excellence, an

independent quasi-governmental organisation

responsible for publishing all clinical guidelines for

the UK National Health Service. This gives explicit

advice regarding diagnosis and management in both

primary and specialist care (and) is easily accessible

to both patients and healthcare practitioners. The

challenge now is to make sure that our scientific

understanding is translated into clinical practice "

(Medical care free of science and based on social

networks. D White).

The problem is that the Wessely School's

interpretation of " scientific understanding " does not

accord with the international evidence, which they

persistently dismiss or disregard.

It is notable that in June 2004, Denton White

was awarded an OBE; the citation was: " For services

to medical education " . Notices circulating at the

time proclaimed him as leading the research into

" CFS/ME " and said his OBE was a " well-deserved

honour and acknowledgement of his contribution to

work on CFS/ME " .

For someone to receive such an honour seems

surprising if the person so honoured is apparently

ignorant of the established facts pertaining to the

subject of his research interest for which he was

honoured.

Conclusion

The NICE Guideline on " CFS/ME " recommends the

national implementation of only behavioural

interventions for such patients, yet the GDG is at

pains to state that it does not regard those

interventions (CBT and GET) as curative or directed

at the underlying disease process (Full Guideline,

page 252). The GDG is careful to state that it makes

no assumptions about aetiology, yet it relies only

upon trials which do make such an assumption (i.e.

that " CFS/ME " is a behavioural disorder). It is not

possible to design any clinical trial without an

assumption of aetiology, and the only " evidence "

that the GDG relied upon was that of Wessely School

psychiatrists whose assumption of " CFS/ME "

aetiology is that it is a somatoform disorder and

whose model is based on fear avoidance and

deconditioning.

For clarification of the precise meaning of the terms

" CBT " and " GET " , the MRC Trials state: " CBT will be

based on the illness model of fear avoidance " and

" GET will be based on the illness model of

deconditioning and exercise intolerance " .

In both instances, the study references claiming to

support these statements are exactly those used

by NICE to support its recommended management

interventions

(http://www.biomedcentral.com/1471-2377/7/6 ).

For an explanation of its recommended therapies,

the Guideline refers readers to the Glossary of Terms

on page 12, which is clear: CBT is " an

evidence-based psychological therapy " and GET is

" an evidence-based approach that involves physical

goal-setting and education. The duration of the

activity is gradually increased (and) is followed by an

increase in intensity. The objective is to improve

the person's CFS/ME symptoms and functioning,

aiming towards recovery " .

That statement is pivotal, because the GDG could

not rationally state that the objective of its

recommended interventions is " aiming towards

recovery " if it had not made the assumption that

" CFS/ME " is a behavioural disorder from which

recovery is possible.

To mislead patients and clinicians alike by implying

that " recovery " is the objective might be deemed a

failure of duty of care, because there is absolutely no

evidence that patients with ME/CFS recover with GET

(but there is significant evidence that some patients

have been actively harmed by it).

This effectively means that NICE is advising

healthcare professionals to tell patients that they

are recommending something which will aid

" recovery " , even though it is not directed at the

underlying disease process. This seems to be clear

evidence that the GDG believes that " recovery " is in

the hands of the patients themselves.

It is the case that psychiatrist Professor White

urged the Guideline Development Group to include

" recovery " as the goal of intervention (see

Stakeholders' Comments on Chapter 6: page 308,

line 6.3.6.16:

http://www.nice.org.uk/nicemedia/pdf/CFSMECommentsTable6.pdf

In the light of so much evidence (not hypotheses) of

serious heart and vascular problems in a subset of

ME/CFS patients (all of which the GDG was directed

to disregard), the question has to be asked: how can

incremental aerobic exercise as recommended in the

NICE Guideline – which is carefully aimed only at

" those who wish to recover " and is to be

" undertaken only with informed consent " , thereby

placing the onus of " recovery " directly on the

patient -- help such patients remain as functional as

possible?

If ME/CFS patients decline to engage with

behavioural modification and incremental aerobic

exercise regimes, no other intervention is offered to

them. They are too often left abandoned, derided,

disparaged and denigrated (see

http://www.meactionuk.org.uk/Quotable_Quotes_Updated.pdf

). By virtue of recommending only behavioural

interventions for all patients with " CFS/ME " , the NICE

Guideline has done nothing to rectify this travesty.

This present document looks at just some of the

evidence about one dysfunctional system in ME/CFS,

the cardiovascular system, but patients suffer to the

same degree with dysfunction in all bodily systems.

ME/CFS is a devastating disorder -- described by the

severely affected patients as " a living death " -- but

the Guideline does not adequately or accurately

reflect the degree of incapacity or severity of illness

experienced on a daily basis by those with ME/CFS.

It is essential to ascertain why such an important

Guideline was deliberately restricted in its remit;

why GDG members were expressly directed not to

consider the totality of the existing evidence-base

and why only those professionals who support the

behavioural model of " CFS/ME " were chosen as GDG

members.

A fundamental question remains: is the Wessely

School's refusal to heed the biomedical evidence

that has been shown by internationally respected

researchers to underpin ME/CFS based on the

psychiatrists' personal involvement with the

medical insurance industry alone, or is it due to

the fact that the biomedical evidence is deemed

inconvenient in the UK because it does not accord

with Government's current policy of off-loading as

cheaply as possible the ever-increasing hordes of

chronically sick who have no commercial value to

the State but who cost it far too much money?

If so, this is surely a short-sighted policy, because it

is well recognised that patients with ME/CFS who are

correctly diagnosed and permitted to rest adequately

in the initial stages are the ones who have hope of

some recovery. If relevant biomedical research were

to be instituted, it would lead to patients being

investigated competently and treated correctly, thus

offering the ME/CFS patient the prospect of being

able to return to an economically productive life,

thereby relieving the State of an ever-increasing

financial burden.

In 2002, the annual cost of ME/CFS to the nation was

said by Lord Clement- to be estimated at £4

billion (Hansard: Lords: 16th April 2002: 898). In

May 2003, a statistical analysis carried out by The

Survey and Statistical Research Centre at Sheffield

Hallam University for the charity Action for ME found

that ME/CFS was costing the nation £3.5 billion per

annum, which is £9.5 million every day ( " Cost to the

Nation Report " , AfME, 12th May 2003).

The latest figures (January 2007) on the economic

impact of ME/CFS in the US are between $22 billion

and $28.6 billion annually; in Japan, the figure is

over $10 billion annually

http://www.meactionuk.org.uk/Facts_from_Florida.htm

To deny the nature, reality and impact of

ME/CFS is a continuing abuse of sufferers.