Friday, July 31, 2009

Research: What do patients want? Why isn't it happening?

 
In response to the many requests, an expanded version of a talk by Dr Neil Abbot given at the Royal Society of Medicine conference, "Medicine and me: ME and CFS - Hearing the patient's voice" in London on Saturday 11 July 2009  is now on the ME Research UK's website at http://www.meresearch.org.uk/information/publications/rsmtalk.html . A text version is given below.

ME/CFS Research: What do patients want? Why isn't it happening?

Introduction

In 2008, the RSM (www.rsm.ac.uk/) hosted a full-day meeting on Chronic Fatigue Syndrome, that focussed mainly on biopsychosocial aspects of the condition, so it is a delight to see a meeting in the 2009 "Medicine and ME" series of events designed to "bring together professionals and patients" to explain and explore some aspects of the illness. It would be marvellous if this led on to a larger RSM-hosted meeting in future years centring on biomedical aspects of the illness and attracting experts from around the world.

The title we were given was "ME/CFS Research: What do patients want to see? Why isn't it happening?" [SLIDE] - a big tent of a topic for a 15 minute presentation.

There's no apology for starting with the wonderful cartoon by Trish Campbell of the Warwickshire Network for ME [SLIDE] since it illustrates the situation many patients find themselves in - a Kafkaesque nightmare involving physical illness compounded by the scepticism of healthcare professionals and the disbelief of family and friends. These two prisoners, hanging from chains in a dungeon, haven't been out to the GP for years; they certainly haven't been properly physically examined for a long, long time; and their quality of life is poor, illustrating what two separate recent reviews have concluded, namely that "...patients exhibit severe, long-term functional impairment. Substantial improvement is uncommon and is less than 6%" (Anderson et al. 2004); and "Full recovery... is rare" (Cairns & Hotopf 2005). But the cartoon also indicates that the management strategies making up the bulk of the "treatments" on offer by the National Health Service in the UK - "CBT and Graded Exercise" as the hanging prisoner says - seem absurd to patients and carers given the problem on the ground. Which brings us to the first suggested answer to the question, "ME/CFS Research: what patients want to see?"

ME/CFS Research: what patients want to see?

a) Less emphasis on psychosocial aspects.
It's not surprising that in an "orphan" illness like ME/CFS there are several hypotheses and proposals to explain how it might be caused or maintained. One of these is the "biopsychosocial model" of ME/CFS, described in the Chief Medical Officer's report of 2002 (see weblink in references) as, "The biopsychosocial model of pathophysiology, applicable to all disease, suggests that once an illness has started its expression is affected by beliefs, coping styles, and behaviours, while consequential physiological and psychological effects act in some ways to maintain and/or modify thedisease process". The limitations of this model, and the evidence-base for its use in ME/CFS have been comprehensively discussed elsewhere (e.g. "The NICE Clinical Guideline: convincing evidence? http://www.meresearch.org.uk/information/publications/NICE_Evidence.pdf ), but it's important to point out that the strategies which it used - cognitive behavioural therapy (CBT) and graded exercise therapy (GET) - are applicable to all illnesses and are therefore not specific to ME/CFS; are used to "manage" symptoms but are not generally thought to be curative per se; and that while the "biopsychosocial" side dominates treatment and research in the UK, its influence is considerably less in the USA where research interest is most intense. As far as research is concerned, most effort in Britain and most if not all Class 1 funding from sources such as the Medical Research Council has gone towards research into the usefulness of CBT and GET [http://www.meresearch.org.uk/information/publications/casetoanswer.html]. Interestingly, a recent meta-analysis of the effect of CBT for ME/CFS showed that, overall, the outcomes of the intervention were mild-to-moderate effect (effect size 0.4; Malouff et al 2008). Indeed, a large body of both professional and lay opinion considers that these are essentially adjunctive techniques, and have little more to offer than good medical care. As Carruthers et al (2003) have pointed out in their superb review: "The question arises whether a formal CBT or GET program adds anything to what is available in the ordinary medical setting. A well informed physician empowers the patient by respecting their experiences, counsels the patients in coping strategies, and helps them achieve optimal exercise and activity levels within their limits in a common sense, non-ideological manner, which is not tied to deadlines or other hidden agenda".
    The scientific literature also contains concerns about many of the "shibboleths" surrounding the influence of psychological factors of various kinds in the development or maintenance of ME/CFS. Two examples suffice.
    The first concerns "somatisation", a term occasionally used to describe ME/CFS or other groups of patients said to focus irrationally on their bodily (somatic) symptoms; these patients, it is said, "experience and communicate somatic distress and symptoms unaccounted for by pathological findings... attribute them to physical illness...and seek medical help for them". However, a recent review (Crombez et al 2009) of patients seeking treatment for pain (a symptom reported by 79% of ME/CFS patients in one large survey, and by 87% of 2,073 consecutive ME/CFS patients in one published study - De Becker et al 2001) concluded "We recommend that researchers... do not use the term somatisation but use the term multiple physical symptoms instead....Making sense of physical symptoms that cannot be explained by current medical models may easily lead to a psychologisation of illness". This paper strikes a particular cord since many patients on the ground do indeed feel shunted towards a psychological explanation for their symptoms early in the assessment process, when a biomedical investigation for the causes of their pain or other symptoms would be most appropriate.
    A second example concerns "personality" and its apparent role in the illness, with some reports claiming rates of personality disorders as high as 40% among patients - some of these claimed personality disorders go under exotic, rather enthralling names, such as "alexithymia" (emotional deficiency), "action-proneness", "learned helplessness", and "histrionic states". However, Belgian investigators (Courjaret et al 2009) recently evaluated the prevalence of "DSM-IV-TR personality disorders" in a sample of 50 women with ME/CFS and, importantly, in two matched control samples. The results showed a striking similarity between the ME/CFS sample and the Flemish healthy control group on various measures, including the prevalence rates of an Axis II disorder (defined as "underlying pervasive or personality conditions, as well as mental retardation") which were 12% in both the healthy Flemish and ME/CFS groups compared with 54% in the psychiatric sample. As the researcher's say, "The results of the present study are unambiguous and straightforward....a person diagnosed with CFS is as (un)likely to have a personality disorder as a subject without CFS".

b) Far more emphasis on Biomedical Research
The corollary of a decreased emphasis on psychosocial research is that focus will turn to biomedical model-based research, in which ME/CFS is seen as "a condition like many other medical conditions where illness results from a specific pathological defect in physiological functioning, mediated at organ, tissue, cellular and/or molecular level, by as yet undefined mechanisms. It...implies that a primary disease entity exists and that the biopsychosocial aspects are consequential" (Chief Medical Officer's report 2002; see weblink in references).

Interestingly, from the UK Clinical Research Collaboration's document, "UK Health Research Analysis (2006)" [http://www.ukcrc.org/PDF/UKCRC_Health_Research_Analysis_Report.pdf] , we have a map of the distribution of total funding spend by research activity in UK, so we know what the pattern of spending looks like in other illnesses and across all illness as a whole. The Kite diagram [SLIDE] shows the proportion of total spend by research activity (indicated at the top of the kite diagram), with data from the 11 largest government and charity funders of health research in the UK. The first import point to note is that the great bulk (68.4%) of all grant spend for all illnesses is to the left of the Kite, i.e. is spent on "aetiology" (research into the risk or cause and development of ill health and diseases) or "underpinning" (research into understanding normal processes and functioning, forming the basis for subsequent investigations) - so the type and distribution of funding that ME/CFS patients want to see is actually the "norm" looking at the global spend in the UK. The second point is that the red areas on this diagram represent many hundreds of millions of points, spent across all illnesses - if the actual UK grant spend in ME/CFS from all sources, charitable included, was drawn on it, it would be a very thin red line indeed (and almost invisible!).
    There is no doubt about the areas of biomedical investigation that need to be targeted - the diagram [SLIDE] flags up "understanding causation and aetiology" and "lab-based and experimental studies" as a the most vital initial steps. And everyone agrees that a "Centre of Excellence" - a single point of reference to which ME/CFS patients could be referred for biomedical assessment and investigation - would be invaluable. Ideally, operating hand-in-glove with such a Centre (providing a ready source of properly diagnosed patients) would be a national ME/CFS Research Centre. There are many templates on which such an entity could be modelled; one example is the BHF Glasgow Cardiovascular Research Centre (GCRC) [http://www.gla.ac.uk/bhfgcrc/], a joint venture between charity and University set up in 2005 with the specific aim of providing a multidisciplinary research environment for their investigation of cardiovascular illnesses.

And there are so many tantalising areas of ME/CFS biomedical research that could be fruitfully explored further [SLIDE]. For example:
(i) Mitochondria: As ME/CFS is characterised by a profound, generalised post-exertional loss of muscle power, it seems reasonable to suggest that mitochondrial dysfunction may be involved; indeed, over the years, there have been number of (necessarily smaller, given the high cost) investigations exploring this aspect and reporting the presence of anomalies. There is indeed a sense that not all is well with mitochondria, and that intriguing findings might well be uncovered from a battery of validated mitochondrial tests from larger sample of well-characterised ME/CFS patients (and controls) and their extended families.
(ii) Infection and immunity: ME/CFS cases are commonly triggered by a viral infection, and the burning question is why an initial infection persists in some people - with serious consequences that can last a lifetime - but not in others. Chronic immune activation has long been thought to be a component of ME/CFS, and there is much diverse evidence (reviewed by Klimas and Koneru 2008 [http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0801C&L=CO-CURE&P=R3325]) that could form the basis of further intense investigation.
iii) Brain and CNS: In historical publications on 'epidemics' of ME, symptoms consistent with central nervous system pathology were reported with regularity, and were as characteristic as the post-exercise malaise, myalgia or the range of other symptoms that patients experienced. It has not yet been established for certain what causes the prominent cognitive dysfunctions in the illness, but factors which might contribute include vascular insufficiency, metabolic dysregulation, or an ongoing infectious process. A range of structural and functional studies to date have had positive findings [http://www.meresearch.org.uk/research/projects/neuroimage.html] that in any other illness would have been explored further. One of the most recent is a report from Cornell University in New York (Mathew et al 2009) showing average lateral ventricular lactate concentrations to be increased almost three-fold in the ME/CFS patients compared with generalized anxiety patients, and 3.5-fold compared with healthy volunteers (both p<0.001), even after controlling for ventricular volume, raising the possibility of a decreased regional cerebral blood flow with consequent increases in brain lactate.
Iv) Vascular: Reports of vascular anomalies have appeared regularly in the scientific literature on ME/CFS over the years. Most recently, the Vascular Diseases Research Unit, University of Dundee, which has received several grants from ME Research UK since 2001, has uncovered unusual sensitivity of the blood flow responses to acetylcholine (a neurotransmitter); increased levels of isoprostanes (a gold standard marker of oxidative stress in the bloodstream); an unexpected increase in dying (apoptotic) white blood cells - consistent with an activated inflammatory process or persistent infection; and increased cardiovascular risk factors with arterial stiffness in ME/CFS patients. On balance, with the observed dyslipidaemia, oxidative stress and inflammation [SLIDE], ME/CFS patients have a lipid profile and oxidant biology that is consistent with but not necessarily accompanied by increased cardiovascular risk. It is surely important that these results are expanded and reproduced by others.
    The point of listing the above is to show the plethora of areas in which further biomedical investigation is warranted. "What patients want to see" is a general advance across a broad range of scientific fronts.

ME/CFS Research: Why "what people want to see" isn't happening? [SLIDE]

(i) ME/CFS not "sexy"
ME/CFS biomedical research is not 'sexy' in scientific terms. Because its profile is low - and coloured by the emphasis on psychosocial aspects of the illness and characterised by disparaging labels ("yuppie flu," "all in the mind") - and because researchers looking in would see little chance of high-level funding, one of the biggest challenges in encouraging established researchers into the field - and attracting fresh young investigators. Interest in researching the illness is increasing (ME Research UK now provides funding to the Universities of Newcastle, Dundee, Strathclyde, Brussels, London - St George's and Hammersmith, Glasgow, and Calgary), yet much more has to be done. In fact, ME/CFS biomedical research really is a fertile field for new discovery, and really is a fresh exciting challenge - and this has to be conveyed and recognised by the wider scientific community.

ii) Scientific/biomedical activity is low-level
One of the striking things about the ME/CFS scientific literature - across all disciplines and models of the illness - is just how small it actually is. To give an example, the absolute number of MEDLINE-listed articles over the past 10 years for the broad subject area "schizophrenia" is approximately 32,800; for "rheumatoid arthritis" 32,000; for "multiple sclerosis" 20,000 - and for ME and CFS together 2500. The discrepancy between the size of the scientific literatures on MS and ME/CFS is even more striking when you consider that the prevalence of MS is between one third and one half that of ME/CFS. Put another way, if ME/CFS elicited the same level of scientific interest as MS, there would have been around 30,000 to 40,000 MEDLINE-listed articles in the past decade instead of the 2500 in actuality. This is what we mean when we say that scientific activity is at a low-level in ME/CFS, and so long as this continues the illness will be disadvantaged. In reality, for breakthroughs to occur, there have to be many, many groups around the world undertaking programmes of research across a range of basic and clinical sciences fields so that a "critical mass" of investigators can produce a "critical mass" of biomedical data.

iii) Lack of continuity
One consequence of the lack of profile of ME/CFS as an illness is that whatever research is, in fact, done tends to be piecemeal and discontinuous. Two simple examples, from the early 1990s, illustrate the point. In the first (Costa et al 1995), blood flow at the brain stem of 43 ME/CFS patients was found to be significantly lower than in healthy controls (p<0.0001) and patients with major depression (p<0.005); a fascinating result which might have clinical significance, but which has never been reproduced with equivalent methodology. In the second (Abbot et al 1994) ME/CFS patients were found to have higher blood levels of CD8, CD38 T cells (markers of immune activation) than controls, and (unexpectedly) there was a strongly positive relationship [SLIDE] between activation markers from patients and their close family contacts. Could it be that an infectious agent affects both patients and household contacts but causes symptoms only in patients, or is the relationship entirely innocent? No-one knows, since follow-on work by independent groups has never been done.
    Funding a smallish pilot studies is one thing, but real breakthroughs come at the end of a programme of painstaking work by a specialist group of researchers. One of the few examples in ME/CFS in the world is the work at the Vascular Diseases Research Unit, University of Dundee, which in a step-by-step progression has uncovered a range of anomalies, but such a progression, following progressive funding, is rare indeed.

iv) Diagnosis: the clinical problem
ME, CFS, CFS/ME and ME/CFS mean different things to different people whether members of the public, or patients, or clinicians or researchers. This problem colours all debate on ME/CFS, yet rather like the whiteness of a wall it is often not recognised as a colour at all. The problem has been alluded to many times (e.g. see "A research and clinical conundrum" [http://www.meresearch.org.uk/information/publications/conferences/spencetalk1.html] but the central point for this discussion is that "diagnostic" difficulties queer the pitch both at the clinic and in the research lab and hinders the progress everyone wants to see.
    The slide is our attempt to describe problem graphically [SLIDE] - though we must be aware that this is only schematic, a way of visualizing the problem which may be more or less complex in reality. While the greatest portion of the circle represents the 'set' of patients with chronic fatigue (CF) - which might represent between 1 and 4% of the population - you can see that the set of patients with CFS (i.e., those with 6-months 'fatigue' plus 4 symptoms) is much smaller (estimated to be 0.2 to 0.4% of the population in the CMO report of 2002), while those with ME as described in the older scientific literature might represent a subset of CFS itself, since post-exercise 'fatigue' is a key element in their illness (population estimates are unavailable for this subset since healthcare professionals no longer diagnose ME per se). The important point is that the each slice melds into the next, and that - in the absence of a full clinical assessment - the popular press, healthcare professionals and medical researchers may easily be deceived about the placing of a particular patient in a particular diagnostic category.
    Fortunately, we have two real examples which illustrate the problems that can arise if investigations to exclude other conditions are not performed before the "diagnosis of exclusion" ME/CFS is given. The first was an audit of 100 consecutive outpatients with CFS in the University of Dundee in 1993: of these patients, 21% were found to have other organic illnesses (e.g. muscle, connective tissue, endocrine disorders); 12% psychiatric disorder alone; and 7% fibromyalgia. The second was an audit of service in 2007 after 3 years at the CFS/ME CNCC in Newcastle: CFS was confirmed in 56% of referrals, but alternative diagnoses were provided in 28%, sleep apnea was diagnosed in 9%, and depression and anxiety in 7%. Thus, it can be seen that in around 40% of patients referred from primary care with a diagnosis of ME/CFS, alterative exclusionary diagnoses can be found after investigation at a specialist clinic.
    For clinicians presented with a heterogeneous group of patients referred from primary care with a "diagnosis" of ME/CFS, the problem can be acute, and was prettily expressed in a recent article by Fischer et al in 2008. Describing a clinic seeing patients with fatigue, exercise Intolerance and Weakness (very like ME/CFS patients), the authors say, "...Sometimes in our Clinic, we feel as if we're wandering through a herd of zebras...Not all the "stripes" on the animals are the same, and not every animal in the herd is actually a zebra...Navigating through clinical complexities is difficult, and we're still learning how to best diagnose and manage our patients".

v) Diagnosis: the research problem
In a biomedical world which prizes 'homogeneous' groups of patients - those with a confirmed diagnosis, sharing similar signs and symptoms and fulfilling strict criteria (such as males aged 30-50 with confirmed HIV infection and a white blood cell count less than 400 CD4/mm3) - the diagnostic mess that is called ME/CFS today is a real complication. In ME/CFS, what we see over and over again are the graphs on the right (the upper, an ideal scenario; the lower from a real biochemical experiment on ME/CFS patients), with the controls nicely tightly packed, and the "CFS" patient measurements much more widely scattered [SLIDE]. There is clearly something going on since the patients have higher values than the controls on average, yet the scatter is problematic, and researchers scratch their heads when they see it. It is therefore important to select for biomedical research studies patients that are well-categorised; i.e., have a full clinical examination (and there is good reason to believe that neuromuscular signs can be found in patients if such assessments are made), and, ideally, be subsetted according to particular criteria - and the subgroups specified by the Canadian definition of ME/CFS [http://www.co-cure.org/cccd.htm] devised in 2003 may come to be seen as a useful starting point for such work.
    Whatever the eventual resolution, this central problem tends to increase the costs of research studies because, ideally, volunteers need to be screened and categorised by medical examination. Interestingly, however, biomedical anomalies can indeed be found in patients diagnosed with ME/CFS, so it may be that careful screening for ME/CFS, with proper exclusion of those with differential diagnoses, is one of the most useful things that can be done.

(vi) Funding for biomedical research in ME/CFS is sparse According to its financial statement of 31st March 2008, Cancer Research UK [http://www.cancerresearch.org.uk/] had an income of £476,559,000 in that financial year. In approximately the same period, ME Research UK's Income was £264,862. Indeed, if all potential charitable sources of funds in the UK were included, the total available charitable spend would not exceed £400,000, a figure which barely covers the cost of one medium-sized clinical trial (which might in fact have an inconclusive result). This is core problem, and the major reason why the biomedical research patients want to see is not happening.
    Big money will be needed to unravel the causes and find cures for ME/CFS. As the diagram shows [SLIDE], some medical research funding in the UK comes from larger national agencies (called "Class 1" funders), such as the Medical Research Council (MRC) and the NHS Research & Development, which allocate funds to established research groups with a track record of success in a certain area, on the basis of a reasonable scientific hypothesis. But getting monies from these larger funders is very difficult, and even if the biomedical investigation of ME/CFS got its 'fair share' of Class 1 funding - something that many of us are still pressing for - that share would fund only a small part of the biomedical activity that is necessary. As most research funding for many, if not all, illnesses comes from charitable sources, i.e. directly or indirectly from public donations, we have to beef up our efforts, increasing funding by a factor of 10--100, and attracting blood and fresh ideas into the field [SLIDE].

References

Abbot NC et al. Immunological findings may vary between populations. British Medical Journal, May 14, 1994

Andersen MM et al. Illness and disability in Danish Chronic Fatigue Syndrome patients at diagnosis and 5-year follow-up. J Psychosom Res 2004;56(2):217-29.

Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue syndrome. Occup Med (Lond). 2005 Jan;55(1):20-31.

Carruthers BM et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome:Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal of Chronic Fatigue Syndrome 2003;11 (1):7-116.

Chief Medical Officer. A Report of the CFS/ME Working Group. Report to the Chief Medical Officer of an Independent Working Group. February 2002. Accessible at: http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4064840

Costa DC. Brainstem perfusion is impaired in ME/CFS. QJM 1995;88:767-73

Courjaret et al. Chronic fatigue syndrome and DSM-IV personality. Journal of Psychosomatic Research 2009;66:13-20

Crombez G et al .The unbearable lightness of somatisation:A systematic review of the concept of somatisation in empirical studies of pain. Pain 2009. Epub ahead of print.

De Becker et al. A definition based analysis of symptoms in a large cohort of patients whith CFS. Journal of Internal Medicine 2001;250:334-40.

Fischer et al. Fatigue, Exercise Intolerance, and Weakness:Lessons in Herding Zebras. Minnesota Medicine, Nov 2008. Accessible at: http://www.minnesotamedicine.com/PastIssues/November2008/CommentaryFisherNovember2008/tabid/2716/Default.aspx

Klimas NG, Koneru AO. Chronic fatigue syndrome:inflammation, immune function, and neuroendocrine interactions. Curr Rheumatol Rep 2007;9(6):482-7.

Malouff JM et al. Efficacy of cognitive behavioral therapy for chronic fatigue syndrome:a meta-analysis. Clin Psychol Rev 2008;28(5):736-45.

Mathew SJ et al. Ventricular cerebrospinal fluid lactate is increased in chronic fatigue syndrome compared with generalized anxiety disorder:an in vivo 3.0 T (1)H MRS imaging study. NMR Biomed 2009;22(3):251-8.

UK Health Research Analysis (2006) UK Clinical Research Collaboration. Accessible at: http://www.ukcrc.org/PDF/UKCRC_Health_Research_Analysis_Report.pdf



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Wednesday, July 29, 2009

Aerobic Capacity

 
[Moderator's Note:
The original post to which this commentary refers can be found at
http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0907d&L=co-cure&P=4177  ]


With reference to the above-titled article recently published by Ali
A. Weinstein et al (5 associated with NIH and 2 with George Mason
University in nearby Northern Virginia):

There are serious problems with this study, reflecting the
limitations of most research I have seen conducted by the U.S.
Government regarding "CFS" (Chronic Fatigue Syndrome).

Right now the best estimate of the prevalence of CFS in the U.S. is
one million patients. CDC's estimate is 4-7 million patients.
Rheumatoid Arthritis (RA) is at least as prevalent; I am not familiar
with the prevalence of Polymyositis (PM).

Surely these researchers could have found more subjects for their
study. They used 9 patients with PM, 10 with RA, and 10 with CFS - 29
patients in all.

The way statistical analysis of this type works is to compare the
difference between the study cohort and a normal cohort, using
information about the mean, the number of subjects, and the variance.

If the study fails to find a statistically significant difference
between the patient group and the control group it has NOT
"disproved" the thesis that there is such a difference (in this case,
it would be a difference in performance on a VO2 MAX stress test).

The study has merely failed to demonstrate such a difference.

In statistical research, the likelihood of finding a significant
result is directly tied to the size of the study.

In this case, with only 9-10 patients in each of the three categories
of disease in this study - and only 29 patients in total, a
statistically significant difference would be a surprise.

The "magic number" for statistical testing is 50. Below that, there
are strong "small sample" problems.

A second error sadly common in government research with regards to
CFS is the apparent lack of familiarity with other studies conducted
on the same subject.

The recent study published by Staci Stevens and others on the same
subject (the VO2 MAX test and CFS) showed that with patients who were
moderately affected with CFS, the scores on a single day of testing
were comparable to those of a sample of normals.

On the SECOND day of the study, however, Stevens found a significant
and large difference in the VO2 MAX score. The CFS cohort scores, on
average, were half those of the matched sample.

This information was readily available to the authors before the
publication of the study.

So the knowledge in the field had already moved beyond testing
patients on just one day, to making use of the CDC-defined symptom of
"post-exertional malaise" in CFS to test their response a second day
- and it was on the second day that the findings were notably robust.

The Weinstein study was outdated on the day it was published; even if
it was not, well-known small sample problems in statistical research
should have cast doubt on the viability of a study that chose 9
patients from a disease that impacts 1 million.

One might even suspect the purpose was to continue to tell a story
about CFS as a "MUPS" illness, using insurance parlance - a syndrome
with "Medically Unexplained Physical Symptoms."

Surely that was not the purpose.

However, NIH now has another dilemma to explain - what's wrong with
all these patients, formerly diagnosed with CFS, who do have abnormal
scores on the VO2 MAX?

Mary M. Schweitzer, Ph.D.
 
 
 
 

Enterovirus and CFS

This article is in the most recent Journal of IiME and is really neat.
It talks about the mechanisms used by enteroviruses to persist long
term in a human host in the apparent absence of infectious virus
particles. It also mentions Chia's CFS-enterovirus work. It starts on
page 23, it wouldn't allow copy and pasting for reposting here.

http://www.investinme.org/Documents/Journals/Journal%20of%20IiME%20Vol%203%20Issue%201%20Screen.pdf

************************************


Journal of IiME - Volume 3 Issue 1 - www.investinme.org

'Human Enteroviruses and Chronic Infectious Disease'
Steven Tracy and Nora M. Chapman

Enterovirus Research Laboratory, Department of Pathology and
Microbiology, University of Nebraska Medical Center, 986495 Nebraska
Medical Center, Omaha, NE, 68198-6495, USA.
stracy@unmc.edu       nchapman@unmc.edu

ABSTRACT

Most of what is known about human enteroviruses(HEV) has been derived
from the study of the polioviruses, the HEV responsible for
poliomyelitis. The HEV are generally not thought to persist for long
periods in the host: an acute, sometimes nasty, infection is rapidly
eradicated by the host's serotype-specific adaptive immune response.

Our discovery that the commonly encountered HEV, the group B
coxsackieviruses(CVB), can naturally delete sequence from the 5' end
of the RNA genome and that this deletional mechanism results in
long-term viral persistence, in the face of the adaptive immune
response, has substantially altered this view.

This previously unknown and unsuspected aspect of enterovirus
replication provides an explanation for previous reports of
enteroviral RNA detected in diseased tissue in the apparent absence of
infectious virus particles.
 
 
 
 

Rapid Response re NICE

Thanks to Ellen Goudsmit for this one!
 
 
Online today (29th July 2009).
bmj.com


Whilst I respect the views of Rawlins and Littlejohns (1), I am not
persuaded that all the NICE guidelines can fairly be described as "robust".
I've worked on about five drafts in the past few years and one of these
included a surprising number of factual errors and demonstrated a distinct
lack of rigour.

The guideline in question concerns the management of chronic fatigue
syndrome (CFS). During the consultation phase, there were at least two
controlled studies supporting multi-component programmes (MCPs), thus
meeting the criteria for recommendation as outlined in the Guidelines Manual
2007. However, one of the trials had been classified under 'behavioural'
interventions although it bore little resemblance to the other studies in
the category (2), the RCT on pacing had been classified under graded
exercise therapy (3) and another study had been downgraded from showing a
positive overall effect to having 'no overall effect', although it still met
the criteria for the former (4).


Since my colleagues and I first alerted NICE to these 'errors', further
studies supporting the efficacy of MCPs have been published (e.g. 5). They
provide therapists with an alternative to the NICE preferred
cognitive-behaviour therapy-based programmes, all of which encourage a
graded increase in activity based on assumptions, not evidence, concerning
the role of deconditioning.
MCPs incorporate several elements of cognitive-behaviour therapy including
strategies to improve sleep and advice regarding diet, activity management
and stress reduction. However, they are more eclectic and make no
assumptions about deconditioning. For instance, graded activity is not
appropriate for 'high-functioning' patients and those with evidence of
ongoing infection (6-7). MCPs permit the practitioner to use pacing to
stabilise the condition and change to graded activity after a period of
sustained improvement. Effect size statistics for MCPs are similar to those
for CBT (4-5), but attrition rates tend to be lower (2 4) so these
programmes are likely to be more cost effective.

The response from NICE to a second request to correct the errors was
rejected as the latter were not considered "sufficiently serious". Space
does not permit me to elucidate further, but a meta-analysis, review,
various surveys and an independent audit have show that the outcomes related
to CBT tend to be modest and that many patients find graded activity
unhelpful (e.g. 8-9). In short, there is a clear need for additional,
evidence based therapeutic options.

One can describe the guideline for CFS in many ways, but robust it is not.

1. Rawlins M, Littlejohns P. NICE outraged by ousting of pain society
president. BMJ 2009, 339, b3028.
2. Taylor RR, Thanawala SG, Shiraishi Y, Schoeny ME. Long-term outcomes of
an integrative rehabilitation program on quality of life: A follow-up study.
J Psychsom Res 2006;61:835-9.
3. Wallman KE, Morton AR, Goodman C, Grove R, Guilfoyle AM. Randomised
controlled trial of graded exercise in chronic fatigue syndrome. Med J Aus
2004;180:444-48.
4. Goudsmit EM, Ho-Yen DO, Dancey, CP. Learning to cope with chronic
illness. Efficacy of a multi-component treatment for people with chronic
fatigue syndrome. Pat Educ Couns 2009, doi:10.1016/j.pec.2009.05.015.
5. Jason LA, Torres-Harding S, Friedberg F, Corradi K, Njoku MG, et al.
Non-pharmacologic interventions for CFS: A randomized trial. J Clin Psych
Med Settings 2007;14:275-96.
6. Chia JKS, Chia AY. Chronic fatigue syndrome is associated with chronic
enterovirus infection of the stomach. J Clin Pathol 2008;61:43- 8.
7. Friedberg F, Sohl S. Cognitive-behavior therapy in chronic fatigue
syndrome: is improvement related to increased physical activity? J Clin
Psychol 2009;65:423-42
8. Malouff JM, Thorsteinsson EB, Rooke SE, Bhullar N, Schutte NS. Efficacy
of cognitive behavioral therapy for chronic fatigue syndrome: a
meta-analysis. Clin Psychol Rev 2008;28: 736-45.
9. Nezu AM, Nezu CM, Lombardo ER. Cognitive-behavior therapy for medically
unexplained symptoms: a critical review of the treatment literature. Behav
Ther 2001;32:537-83.


Competing interests: None declared
 
 
 
 
 

Sunday, July 26, 2009

Post-Injury CFS

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INjURYBoard.com
Promoting Safety, Protection Rights


Head & Brain Injuries



Fatigue As The
Result of Personal Injury



Posted by Wayne Parsons

July 24, 2009 4:26 PM

Tags: fatigue, chronic fatigue syndrome, pain, injury,
wage loss, income, work, personal injury, Parsons,
Honolulu, Hawaii



Everyone knows about broken bones, lacerations,
traumatic brain injury [ http://bit.ly/13eNhq ], loss of
vision, spinal cord injury and other physical injuries
that follow automobile accidents, medical
malpractice, construction site accidents and product
defects.

One often ignored after effect is fatigue that can
become chronic: chronic fatigue syndrome (CFS)
[ http://bit.ly/p3bbl ].


Surveys of injured persons often show that fatigue is
one of the most significant long term permanent
effects of an injury and in particular injury that
results in chronic pain.

Fatigue, like pain, doesn't show up on an x-ray and
doctors rarely spend any time trying to help with
fatigue. Even when the pain is recognized as an
issue, fatigue is often left out of the list of
disabilities.





      Chronic fatigue syndrome (CFS) is an
      illness defined by disabling physical and
      mental fatigue and physical and mental
      symptoms that are not explained by
      conventional medical and psychiatric
      diagnoses.

      CFS affects between 400,000 and
      800,000 people in the United States and
      has an average duration of 5 years, but
      symptoms can persist as long as 20
      years.

      The prognosis for recovery of severely ill
      CFS patients is poor.

      Despite CFS's disabling, enduring, and
      prevalent nature, scant studies have
      quantified its impact on the health and
      well-being of those affected, on the
      health care system, or on society as a
      whole.



      The burden of CFS is poorly recognized,
      and the illness remains an inadequately
      managed health problem.

      Two population-based studies of CFS
      have been conducted in the United
      States, and both found that CFS is one of
      the more common chronic illnesses
      among women across all racial/ethnic
      groups and that less than 20% of those
      who suffer from CFS have been
      diagnosed by a health care provider.

      Only three studies, all of which were
      clinic based, have attempted to quantify
      the impact of CFS, and each showed that
      people with the syndrome were likely to
      have lost their job or to be unemployed.

      In addition, it was shown that persons
      with CFS pose a disproportionate burden
      on the health care system and their
      families since they are sick for long
      periods of time and since there is no
      known cure for the illness.




The ability of an injured person to get back to a
functional life is often affected most severely by
fatigue. even when a person is physically able to lift
and bend and do the tasks of many jobs, the
consequence of fatigue is that the person can't keep
any job because fatigue takes them out of a 40 hour
work week.

As reported in the study The economic impact of
chronic fatigue syndrome [ http://bit.ly/p3bbl ] by
Kenneth J Reynolds, Suzanne D Vernon, Ellen
Bouchery and William C Reeves, SRA International,
Inc., Arlington, U.S.A, Division of Viral and
Rickettsial Diseases, Centers for Disease Control and
Prevention, Atlanta, U.S.A, The Lewin Group, Falls
Church, U.S.A:




      The magnitude of the economic impact
      imposed on the individual and on society
      by CFS is substantial. Approximately
      one-quarter of persons with CFS, who
      would otherwise have participated in the
      labor force, ceased working. For those
      who continued to work, average income
      declined by one-third.

      This represents an estimated annual loss
      of almost $20,000 for the individual
      suffering from CFS. This magnitude of
      loss approximates half of their labor
      force and household productivity in a
      given year.

      The $9.1 billion national loss is
      comparable to that estimated for other
      illnesses, such as digestive system
      illnesses ($8.4 B) and infectious and
      parasitic diseases ($10.0 B) [19] and is
      greater than the estimated productivity
      losses from immunity disorders ($5.5 B),
      nervous system disorders ($6.4 B), or
      skin disorders ($1.3) [23].

      This estimate does not include health
      care costs, which are likely to be
      substantial and does not address
      reductions in quality of life, which are
      likely to be large due to the debilitating
      fatigue.



      We estimated annual lost productivity.
      However, CFS is a chronic illness. The
      average duration of CFS identified in
      population studies is 5 years and most
      patients with CFS seen by health care
      providers have been ill for more than 6
      years.

      Thus, productivity losses, health care
      expenses, and reductions in quality of life
      continue for many years for most
      affected individuals and thus would have
      a substantial long-term impact on the
      standard of living of individuals with CFS
      and their family members.



It often starts with pain that doesn't go away and
lingers and tortures the injured person 24 hours a
day, 7 days a week as reported in a Time Magazine
feature article The Right (and Wrong) Way to Treat
Pain [ http://bit.ly/3ewour ] by Claudia Wallis.




      With chronic pain, however, the alarm
      continues to shriek uselessly long after
      the physical danger has passed.

      Somewhere along the line--maybe near
      the initial injury, maybe in the spinal cord
      or brain--the alarm system has broken
      down.

      What researchers have only recently
      come to understand is that prolonged
      exposure to this screaming siren actually
      does its own damage.

      "Pain causes a fundamental rewiring of
      the nervous system," says Dr. Sean
      Mackey, director of research at Stanford
      University's Pain Management Center.

      "Each time we feel pain, there are
      changes that occur that tend to amplify
      our experience of pain."

      That is why it is a mistake, despite our
      grin-and-bear-it tradition, to ignore or
      under treat severe pain.



Fatigue is often the most disabling feature of chronic
pain. The injured person is often told by the
insurance company, their employer or even their own
attorney that they can go back to work and so they
have no claim for future wage loss.
On top of that their fatigue is ignored and not
understood to be a part of the injury. It is treated
like a form of laziness or lack of initiative.

The treating doctor has probably told them that they
can physically do the work at their old job or at least
at some other less strenuous job.

What is missing in this analysis is that if the injured
person suffers from fatigue they cannot do the work
if it involves a 40 hour job.


Unless a careful workup is done of the existence of
fatigue and the connection of fatigue to the injury,
the injured person will not be compensated for what
can be a significant loss of future earnings.

What needs to be done is an analysis of the injured
person by a neuropsychologist or other doctor using
The Universal Work Skills Evaluation test.

Below is a video showing a truck driver taking the
test. Although there is no sound the test shows that
the person has chronic fatigue.




Work Skills Evaluation for Michigan Truck Accident
Victim Who Was Awarded a $5.65 Million Verdict:

http://bit.ly/8YbDN


Doctors have several ways of validating fatigue as a
disabling factor resulting from personal injury.