The Role of Viruses in ME/CFS, XMRV and the MRC PACE Trial: Margaret Williams 21 November 2009

The Role of Viruses in ME/CFS, XMRV and the MRC PACE Trial – Margaret Williams – 21st November 2009

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Note:  This is a long and heavily formated document and I am posting only the introduction here:

The full document can be accessed here on MEActionUK website:

http://www.meactionuk.org.uk/The-role-of-viruses-in-ME.htm

http://tinyurl.com/ykjveep

http://www.meactionuk.org.uk/The-role-of-viruses-in-ME.pdf

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The role of viruses in ME/CFS: what, if any, will be the effect of the discovery linking XMRV to ME/CFS on the MRC PACE Trial?

by Margaret Williams

21 November 2009

For decades it has been known and shown that viruses play a role in ME/CFS; some illustrations from the literature are provided below (all of which are relevant and significant).

In relation to “CFS”, the most-studied viruses have been the Epstein-Barr Virus (EBV) and the Human Herpes Virus-6 (HHV-6). In relation to “pure” ME, the most studied viruses (and for which there is extensive evidence) have been the enteroviruses, usually Coxsackie B (CBV). Some illustrations from the literature of the role that viruses play in ME/CFS are provided at the end of this paper; all are significant.

There is increasing awareness that the dysregulated immune system that is a hall-mark of ME/CFS allows multiple latent viruses and microbial agents to become reactivated (Co-Cure NOT:12th November 2009).

Moreover, recent research has shown that even viruses which were hitherto believed not to persist after an acute infectious episode are capable of long-term viral persistence.

Nora Chapman et al from the Enterovirus Research Laboratory, Department of Pathology and Microbiology, University of Nebraska Medical Centre, have shown that human enteroviruses Coxsackie B can naturally delete sequence from the 5’ end of the RNA genome and that this deletional mechanism results in long-term viral persistence, which has substantially altered the previously held view

(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2440640/?tool=pubmed ). In a specially commissioned piece for the charity Invest in ME, the researchers say: “This previously unknown and unsuspected aspect of enterovirus replication provides an explanation for reports of enteroviral RNA detected in diseased tissue in the apparent absence of virus particles” (Journal of IiME 2009:3:1).

Dr John Chia, an infectious diseases specialist from Torrance, California, who specialises in ME/CFS, is on record: “I believe that the main reason (ME)CFS patients are symptomatic is due to continuing inflammatory response toward viruses living within the cells, enteroviruses in most of the cases I see. We have clearly documented certain enterovirus infections triggering autoimmune responses in some patients…Can you imagine how we would feel if there are viruses surviving in our muscles, brains, hearts and gastrointestinal tracts triggering ongoing immune responses?”  
(http://aboutmecfs.org/blog/?p=865 ).

The CFIDS Chronicle (Research Update, Summer 1993) explained viruses and retroviruses as follows:

“A virus is a microscopic organism that lives within the cells of another living organism. Viruses cause disease at the most basic level, by damaging the cells of living things. By themselves, viruses are lifeless particles incapable of reproduction, but once they enter the cell of another living thing they become active organisms that can multiply hundreds of times.

“Viruses are comprised of two parts – a core of either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and a protective envelope of protein. RNA viruses are smaller than DNA viruses and sometimes contain a special enzyme called reverse transcriptase which allows them to convert RNA to DNA. These specialised viruses are known as retroviruses and have a unique ability to merge with the host’s own genetic material.

“Retroviruses have the unique ability to replicate themselves by (i) making a double-stranded DNA copy called a ‘pro-virus’ once they enter living cells. Pro-viruses integrate themselves into the human chromosome and become part of the host’s genetic code (ii) alter the host’s immune response by evading detection as a ‘hidden invader’ (iii) remain hidden and latent, spliced within the host’s DNA, for long periods of time. Retroviruses are known to be potent stimulators of cytokines”.

On 8th October 2009 the premier journal Science published a paper online showing a direct link between a retrovirus and ME/CFS (Detection of infectious retrovirus XMRV, in blood cells of patients with chronic fatigue syndrome. Lombardi VC, Ruscetti FW, Peterson DL, Silverman RH, Mikovits JA et al) which caused global reverberations.

However, this was not the first time that a retrovirus had been associated with ME/CFS.

In 1991, using polymerase chain reaction and in situ hybridisation, Dr Elaine De Freitas, a virologist at the Wistar Institute, Philadelphia (which is America’s oldest independent institution devoted to biological research) and Drs Daniel Peterson, Paul Cheney, David Bell et al found such an association (Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci USA 1991:88:2922-2926). It is notable that co-author Hilary Koprowski is a distinguished virologist and Professor Laureate who was Director of the Wistar Institute from 1957-1991; he is a member of the US National Academy of Sciences and is Director of the Centre for Neurovirology at Thomas Jefferson University.

Before publication, the findings were presented on 4th September 1990 by Elaine De Freitas at the 11th International Congress of Neuropathology in Kyoto, Japan.

Ten days later, on 14th September 1990 Dr Peter White (as he then was) and other members of the Wessely School dismissed the findings: “in the vast majority of CFS cases there is a psychological component. About 75% of CFS sufferers are clinically depressed, according to Peter White, senior lecturer in the department of psychiatric medicine at St Bartholomew’s Hospital in London. White said he believes depression is often a cause, rather than a consequence, of CFS…Les Borysiewicz, a clinical virologist at Addenbrookes Hospital in Cambridge (now Chief Executive of the MRC, having succeeded Professor Colin Blakemore) (said) ‘Whatever causes CFS, it isn’t the virus itself’…Anthony Clare, psychiatrist and medical director of St Patrick’s Hospital in Dublin (now deceased), pointed out that…there have been many ‘fatigue’ diseases with shifting causes: ’Neurasthenia, food allergies, now viruses. Some people would always rather have a disease that might kill them than a syndrome they have to live with’ ” (Science 1990:249:4974:1240).

In their PNAS article that was published in April 1991, De Freitas et al noted that chronic fatigue immune dysfunction syndrome (CFIDS) “may be related or identical to myalgic encephalomyelitis” and examined adult and paediatric CFIDS patients for evidence of human retroviruses (HTLV types I and II). As the CFIDS Chronicle article noted, the Wistar team looked at the peripheral blood DNA to see if they could find messenger RNA (mRNA) encoding for a viral segment of the HTLV-II virus.

At that time, known human retroviruses were the human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2) which are known to cause AIDS, and human T-lymphotropic viruses HTLV-I which causes lymphoma and HTLV-II which causes leukaemia (Hunter-Hopkins ME-Letter, October 2009). The four segments of the HTLV-II virus are referred to as the env, gag, pol and tax.

After a two year study, De Freitas et al provided evidence for HTLV-II-like infection of blood cells from CFIDS patients (and also to a lesser extent from people closely associated with them). This evidence was further substantiated by patient reactivity to proteins with the molecular weights reported for HTLV-I and HTLV-II antigens.

In their article, De Freitas et al said: “The frequency of these antibodies in CFIDS patients compared with healthy non-contact controls suggests exposure / infection with an HTLV-like agent rare in healthy non-contact people”.

Following the Wistar findings, researchers at the US Centres for Disease Control (CDC) allegedly attempted to replicate De Freitas’ work but failed to do so; this was suggested to be because certain scientists appeared eager to discount any possibility of a retroviral association with CFIDS. De Freitas defended her work and insisted that the CDC investigators had modified her assays, with the result that her work could not be replicated by the CDC.

De Freitas was publicly discredited; her research funding was discontinued and her research abandoned; she was subjected to what appeared to be attempts to destroy her professional reputation. Commenting on the subsequent discovery of XMRV (see below), ME/CFS expert Dr Paul Cheney of The Cheney Clinic was unambiguous: “Her work was unfortunately assaulted by the CDC. Her proposal to fly to the CDC in Atlanta to physically run the assays side by side with the CDC scientists was dismissed by the CDC” (http://cheneyclinic.com/a-retrovirus-called-xmrv-is-linked-to-cfs/538  ).

Read full article here:

http://www.meactionuk.org.uk/The-role-of-viruses-in-ME.htm

http://tinyurl.com/ykjveep

http://www.meactionuk.org.uk/The-role-of-viruses-in-ME.pdf

http://tinyurl.com/y8m8s8h

Prof Peter D White: Neurology and Psychiatry SpRs Teaching Weekend

Prof PD White: Neurology and Psychiatry SpRs Teaching Weekend

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14 November 2009

THE BRITISH NEUROPSYCHIATRY ASSOCIATION

http://www.bnpa.org.uk

http://bnpa.org.uk/doc/HANDBOOK.pdf

Neurology and Psychiatry SpRs Teaching Weekend

12 to 14 December 2008 St Anne’s College – Oxford

THE ESSENTIALS OF NEUROPSYCHIATRY

Presentations:

[...]

09:50 Chronic fatigue syndrome: neurological, psychological or both?

Peter White, Professor of Psychological Medicine, Barts and the London Medical School

The extract I am appending is a summary of Professor Peter Denton White’s presentation (Page 46 of PDF) in which he talks about the taxonomy of CFS “being a mess”.

During his Royal Society of Medicine “CFS” Conference presentation, in April 2008, White had said, ominously:

“…So ICD-10 is not helpful and I would not suggest, as clinicians, you use ICD-10 criteria. They really need sorting out; and they will be in due course, God willing.”

See unofficial transcript of part of White’s RSM presentation, here, in which he presents his thoughts on current ICD taxonomy:

Prof Peter White discouraging RSM Conference from using ICD-10: http://tinyurl.com/PDW-RSM-ICD-10

In an April 2009 paper, co-authored by White, the authors propose a change to current ICD-10 codings:

http://www.ncbi.nlm.nih.gov/pubmed/19366500

Psychological Medicine Preprint “Risk markers for both chronic fatigue and irritable bowel syndromes: a prospective case-control study of primary care”

In the section “Implications for Further Research” the authors state that because the paper finds that:

“These data also suggest that fatigue syndromes are heterogeneous (Vollmer-Conna et al. 2006), and that CFS/ME and PVFS should be considered as separate conditions, with CFS/ME having more in common with IBS than PVFS does (Aggarwal et al. 2006). This requires revision of the ICD-10 taxonomy, which classifies PVFS with ME (WHO, 1992)”

 Presentation given at Neurology and Psychiatry SpRs Teaching Weekend

http://bnpa.org.uk/doc/HANDBOOK.pdf

[Extract]

Presentation:

Chronic fatigue syndrome: neurological, psychological or both?

Peter White, Professor of Psychological Medicine, Barts and the London Medical School

Epidemiology of fatigue and CFS

Fatigue is a common symptom in both the community and primary care. When asked, between 10 and 20 per cent of people in the community will report feeling abnormally tired at any one time.

At the same time, fatigue is continuously distributed within the community, with no point of rarity.

Therefore any cut-off is arbitrary and the prevalence will vary by how the question is asked, the symptom volunteered, and its context. Between 1.5 % and 6.5 % of European patients will consult their general practitioner with a primary complaint of fatigue every year, the incidence varying by age and population. Fatigue is more commonly reported and presented to general practitioners by women and the middle-aged, and is most closely associated with mood disorders and reported stress. It does not seem to vary by ethnicity in the UK, but there is an intriguing paradox in that it is reported more commonly by those in high income countries, yet is presented to medical care more often in low income countries.

Prolonged or chronic fatigue is significantly less common than the symptom of fatigue and it is only in the last 10 years that consensus has emerged about the existence of a chronic fatigue syndrome (CFS), also called myalgic encephalomyelitis (ME). CFS is now accepted as a valid diagnosis by medical authorities in the UK, in the United States of America, as well as internationally. About one third of patients presenting to their doctor with six months of fatigue will meet criteria for a chronic fatigue syndrome. The other two thirds have fatigue secondary to another condition, most commonly mood and primary sleep disorders. Its primary symptom is fatigue, both physical and mental, which particularly follows exertion. Other symptoms agreed in consensual guidelines include poor concentration and memory, sleep disturbance, headache, sore throat, tender lymph glands, muscle and joint pain.

There are several criterion based definitions of CFS. These definitions were derived by consensus and have not been supported by empirical studies, and continue to be refined. Their utility stems from providing reliable criteria for research studies, rather than clinical use. The prevalence of CFS is between 2.5 % and 0.4 % depending on the definition used and whether comorbid mood disorders are excluded (that is mood disorders that are not thought to be the primary diagnoses). It is most common in women, the middle-aged, and ethnic minorities (unlike fatigue) – at least in English speaking countries.

The diagnosis and classification of CFS

The clinical taxonomy for CFS is a mess. The ICD-10 classification defines CFS within both the neurology chapter and mental health chapters. Myalgic encephalomyelitis, the alternative name for CFS, is classified as a neurological disease (G93.3) (a.k.a. post-viral CFS), whereas neurasthenia (a.k.a. CFS not otherwise specified) is classified within mental health (F48).

[Ed: Note that White does not mention, here, that Chronic fatigue syndrome is listed in ICD-10: Volume 3, The Alphabetical Index* at G93.3, the same coding as for Benign myalgic encephalomyelitis, and for Postviral fatigue syndrome (ICD-10: Volume 1: The Tabular List).]

*ICD-10: Volume 3, The Alphabetical Index:
http://www.scribd.com/doc/7350978/ICD10-2006-Alphabetical-Index-Volume-3

[Back to PDW]

(Incidentally, this mess is not specific to CFS, since there are several conditions within the neurology chapter of ICD-10 that are also classified in the mental and behavioural disorders chapter. For instance, Alzheimer’s disease is classified within neurology, whereas dementia due to Alzheimer’s disease is classified under mental health. My personal view is that it is high time that all mental health disorders and neurological diseases affecting the brain were classified within the same chapter, simply called diseases/disorders of the brain and nervous system.)

[Ed: The WHO Department of Mental Health and Substance Abuse, which is overseeing the revision of Chapter V (Mental and Behavioural Disorders), is also managing the technical part of the revision of Chapter VI (Diseases of the Nervous System). According to Dr Geoffrey Reed, Senior Project Officer, WHO Department of Mental Health and Substance Abuse, Proposal forms for ICD Chapter V and Chapter VI are in preparation and expected to be released shortly.]

[Back to PDW]

There is also a current debate between “lumpers” and “splitters” about the nosology of “functional” somatic syndromes (symptom defined conditions), such as CFS, IBS and “fibromyalgia”. Some argue that the close associations between the syndromes (those with CFS are also more likely to have fibromyalgia and/or IBS) argues in favour of their being different manifestations of one over-arching functional somatic syndrome (the “lumpers”). Others argue that these syndromes are best understood by exploring their heterogeneity (the “splitters”). There is evidence to support both arguments, but two large and recent epidemiological studies suggest that chronic unexplained fatigue, for one, is both associated with and separate from other “functional” somatic syndromes. In particular, predisposing risk factors are shared whereas triggering factors are different.

CFS is not an easy diagnosis to make, since misdiagnosis is common in patients diagnosed as having CFS. A recent audit of my CFS clinic revealed that 4 out of 10 new patients (n = 250) assessed did not have CFS, and that was after a third of referrals had already been rejected as not being CFS.

The most common misdiagnoses were mood disorders, especially depressive disorders, and primary sleep disorders, particularly sleep apnoea. Other misdiagnoses included coeliac disease and autoimmune conditions. Alternative neurological diagnoses were made in 2%.

Aetiology and pathophysiology

The aetiology of CFS is unknown, but there is evidence that different risk markers are associated with predisposition, triggering, and maintenance of the illness. Predisposing risk markers include female sex, middle age, mood disorders (especially depressive disorders), other symptom defined syndromes, such as irritable bowel syndrome, and possibly either sedentary behaviour or excessive activity. As might be expected CFS patients are more likely to have attended their GP, than healthy matched controls, even up to 15 years before onset, but recent work shows that those with IBS (and no CFS) have the same tendency.

Triggering risk markers are less well established, but there is sufficient evidence to support certain infections as aetiological factors not only for fatigue but also CFS, with the best replicated evidence supporting a role for Epstein-Barr virus infection, which triggers CFS in 10% of those infected.

Maintaining or perpetuating risk markers are most important in determining treatment programmes, since reversing maintaining factors should lead to improvement. Reasonably well established factors include mood disorders, such as dysthymia, illness beliefs such as believing the whole condition is physical, pervasive inactivity, avoidant coping, membership of a patient support group, and being in receipt of or dispute about financial benefits.

Few pathophysiological findings in CFS have been replicated in independent studies. Those that have been include down-regulated hypothalamic pituitary-adrenal axis, physical deconditioning, and discrepant reports between perception of symptoms and disability and their objective tests.

The latter finding is now supported by functional brain scanning studies suggesting altered brain activity with specific tasks. The discrepancy between subjective states and objective tests has been found before in other symptom defined syndromes, such as “fibromyalgia”, and may be related to enhanced interoception (the perception of visceral phenomena), a concept first described by Charles Sherrington in 1904. One hypothesis currently being tested is that the common predisposition to “functional” somatic syndromes is caused by enhanced interoception.

Recent work suggests that these factors may be reversed by rehabilitation.

Prognosis

Without treatment the prognosis of CFS is poor with a systematic review of outcomes finding the median full recovery rate was 5 % (range 0-31%) and the median proportion of patients who improved of 39.5% (range 8-63%). Being younger, having less fatigue baseline, a sense of control over symptoms and not attributing illness to a physical cause were all associated with a better outcome. The prognosis is considerably better after treatment.

Treatment

The NICE guidelines, published in 2007, were based on an updated systematic review. The essence of specialist care is rehabilitation, provided on an individual basis with an appropriately qualified and trained therapist. The two approaches with the greatest evidence of efficacy are cognitive behaviour therapy (CBT) and graded exercise therapy (GET). Approximately 60% of patients report significant improvement with these approaches and about 25%report full recovery, which lasts. No pharmacological treatments are recommended (antidepressants are ineffective), but symptomatic pharmacotherapy for specific symptoms (such as pain) or comorbid conditions such as depressive illness) can be helpful complementary treatments.

These rehabilitation approaches have not received universal approval from patient charities, with concerns that patients may be harmed by exercise therapies or that CBT implying that the condition is psychological.

Is CFS neurological or psychological?

This is a nonsensical question when one considers the neuroscience of consciousness and recent advances in functional brain physiology. The philosopher, John Searle, stated the answer to this Cartesian dualism that still bedevils western medicine. “Conscious states are caused by neurophysiological mechanisms, and are realised in neurophysiological systems.” Therefore it is not possible to have a psychological process or event without a neurological mediating process. It is neither of the mind or body; it is both.

Fatigue secondary to neurological diseases

Fatigue is commonly associated with chronic medical disorders, but it should be differentiated from fatiguability. Fatiguability is the onset of a physical sensation of fatigue and weakness after exertion and is commonly reported with neurological diseases such as multiple sclerosis and myopathies.

Apart from measures of disease activity, other associations of secondary fatigue in general that have been repeatedly found include sleep disturbance, mood disorders, inactivity and physical deconditioning. Studies of fatigue associated with multiple sclerosis are instructive and exemplary. As in all studies of secondary fatigue, measures of the severity or pathophysiology of the disease itself are associated with fatigue. Some cytokines are associated, but others are not.

Associations vary depending on the fatigue measure, confirming the multidimensional nature of fatigue, but all measures are associated with depression. Objectively confirmed sleep disturbance is also associated with fatigue. Fatigue associated with MS therefore requires biopsychosocial management.

There have been a number of studies of various treatments aimed at reversing the associations of secondary fatigue in general, in the hope they would help fatigue directly, with variable results. As with CFS, the most consistent evidence of efficacy has been with graded exercise programmes and CBT.

Attarian HP, Brown KM, Duntley SP, et al. The relationship of sleep disturbances and fatigue in multiple sclerosis. Arch. Neurol. 61 (2004), 525-8.

Baker R, Shaw EJ. Diagnosis and management of chronic fatigue syndrome or myalgic encephalomyelitis (or encephalopathy): summary of NICE guidance. BMJ 2007 doi: 10.1136/bmj.39302.509005. AE

Chambers D, Bagnall A-M, Hempel S, Forbes C. Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review. J R Soc Med 2006;99:506-20.

Cleare AJ. The neuroendocrinology of chronic fatigue syndrome. Endocr. Rev. 24 (2003), 236-52.

Flachenecker P, Bihler I, Weber F, et al., Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Mult. Scler. 10 (2004), 165-9.

Fulcher KY, White PD. Strength and physiological response to exercise in patients with the chronic fatigue syndrome. J. Neurol. Neurosurg. Psychiatry 69 (2000), 302-7.

Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue and chronic fatigue syndrome: a systematic review. Q. J. Med. 90 (1997), 223-33.

Kroencke DC, Lynch SG, Denney DR. Fatigue in multiple sclerosis: relationship to depression, disability, and disease pattern. Mult. Scler. 6 (2000), 131-6.

Lyall M, Peakman M, Wessely S. A systematic review and critical evaluation of the immunology of chronic fatigue syndrome. J. Psychosom. Res. 55 2003), 79-90.

National Institute for Health and Clinical Excellence. Clinical guideline CG53. Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management. London, NICE, 2007. http://guidance.nice.org.uk/CG53.

Reeves WC et al. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution.BMC Health Serv Res 3 (2003), 25.

Romani A, Bergamaschi R, Candeloro E, et al., Fatigue inmultiple sclerosis: multidimensional assessment and response to symptomatic treatment. Mult. Scler. 10 (2004), 462-8.

M. C. Tartaglia, S. Narayanan, S. J. Francis, et al., The relationship between diffuse axonal damage and fatigue in multiple sclerosis. Arch. Neurol. 61 (2004), 201-7.

Wessely SC, Hotopf M, Sharpe M. Chronic Fatigue and its Syndromes (Oxford: Oxford University Press, 1998).

Wessely S, Nimnuan C, Sharpe M. Functional somatic syndromes: one or many? Lancet 354 (1999), 936-9.

Wessely S, White PD. In debate: there is only one functional somatic syndrome. Br. J. Psychiatry 185 (2004), 95-6.

White PD, Thomas JM, Kangro HO, et al., Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis. Lancet 358 (2001), 1946-54.

White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; on behalf of the PACE trial group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol 2007;7:6.

[ Extract ends, doc: http://bnpa.org.uk/doc/HANDBOOK.pdf ]

For detailed information on the proposed structure of ICD-11, the Content Model and operation of iCAT, the collaborative authoring platform through which the WHO will be revising ICD-10, please scrutinise key documents on the ICD-11 Revision Google site:
https://sites.google.com/site/icd11revision/
https://sites.google.com/site/icd11revision/home/documents

For information around the DSM and ICD revision processes see DSM-V and ICD-11 Directory page: http://meagenda.wordpress.com/dsm-v-directory/

Suzy Chapman
http://meagenda.wordpress.com
http://twitter.com/MEagenda

More evidence of inflammation in (ME)CFS: M Williams 14 November 2009

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Update: I am advised that the PDF referenced in the text of Ms Williams’ article, below, is no longer available at the URL given. A cached html version of the document has been archived here:

http://www.meactionuk.org.uk/Infectious-mononucleosis-as-a-model-for-chronic-fatigue-syndromes.htm

Permission to Repost

http://www.meactionuk.org.uk/More-evidence-of-inflammation-in-(ME)CFS.htm

http://www.meactionuk.org.uk/More-evidence-of-inflammation-in-(ME)CFS.pdf

More evidence of inflammation in (ME)CFS

Margaret Williams

14 November 2009

In his presentation in Bergen on 20th November 2009, Professor Peter White’s power point slides state about (ME)CFS that maintaining factors include illness beliefs, the search for legitimacy, being on benefits, and the diagnostic label, and that immune or viral measures are NOT involved in the maintenance of the disorder

( http://www.unifobhelse.no/upload/Bergen%20What%20is%20CFS%202009.pdf )

White’s assertion that immune or viral measures are not involved in the maintenance of the disorder would seem to be a direct denial of the evidence of two of the world’s leading immunologists who specialise in ME/CFS, Professors Mary Ann Fletcher and Nancy Klimas, who recently published yet more confirmatory evidence of immune dysfunction in the maintenance of the disorder (Journal of Translational Medicine 2009:7:96: doi:10.1186/1479-5876-7-96). Their peer reviewed article was published immediately upon acceptance.

Fletcher and Klimas et al are clear that cytokine abnormalities are common in (ME)CFS and that the cytokine changes observed are more likely to be indicative of immune activation and inflammation, rather than specific for (ME)CFS, as people with fibromyalgia, Gulf War Illness, rheumatological disorders and multiple sclerosis may also have similar cytokine patterns.

The authors do, however, demonstrate that several of the abnormal cytokines show promise as potential biomarkers for (ME)CFS.

As Fletcher and Klimas et al point out:

“CFS studies from our laboratory and others have described cytokine abnormalities. Other studies reported no difference between (ME)CFS and controls. However, methodologies varied widely and few studies measured more than 4 or 5 cytokines. Multiplex technology permits the determination of cytokines for a large panel of cytokines simultaneously with high sensitivity.

“In this study, 10 of 16 cytokines examined showed good to fair promise as biomarkers. However, the cytokine changes observed are likely to be more indicative of immune activation and inflammation…Many of the symptoms are inflammatory in nature.

“There is a considerable literature describing immune dysfunction in (ME)CFS.

“The goal of this study was to determine if, using new technology, plasma cytokines had sufficient sensitivity and specificity to distinguish (ME)CFS cases from age-matched healthy controls….Amounts of cytokines in plasma or serum are often below the level of detection in traditional ELISA assays.

“The availability of sensitive multiplex technology permitted the determination of 16 cytokines simultaneously…In the (ME)CFS cases, we found an unusual pattern of the cytokines that define the CD4 T cell.

“Pro-inflammatory cytokines: A significant elevation in the relative amounts of 4 of 5 pro-inflammatory cytokines in peripheral blood plasma of patients with (ME)CFS was found when compared with the controls. In cases, lymphotoxin (LT)a was elevated by 257% and IL-6 by 100% over the controls.

“TH2 cytokines: Both interleukin (IL)-4 and IL-5 were elevated in (ME)CFS, with the median of IL-4 (being) 240% and of IL-5 (being) 95% higher in cases than controls.

“Anti-inflammatory cytokines: IL-3 was significantly lower in (ME)CFS patients.

“TH1 cytokines: IL-12 was significantly elevated (120%) and IL-15 decreased (15%) in cases compared to controls.

“IL-8 (CXCL8): this chemokine was 42% lower in the (ME)CFS patients.

“Along with the TH1 abnormalities, we found up-regulation of TH2 associated cytokines, IL-4 and IL-5, in the (ME)CFS subjects. Allergy is common in (ME)CFS cases. Years ago, Straus et al reported >50% atopy in 24 CFS patients.

“The probability of chronic inflammation in (ME)CFS patients is supported by the elevation of four members of the pro-inflammatory cytokine cascade , LTa, IL-1a, IL-1b and IL-6, in the (ME)CFS samples compared to controls.

“Interleukin-13, associated with inhibitory effects on inflammatory cytokine production, was lower in cases compared to controls.

“The inflammatory mediator IL-8 (a chemokine known as CXCL8) known to be responsible for migration and activation of neutrophils and NK cells was decreased in plasma of (ME)CFS patients.

“The observations of abnormal cytokine patterns in (ME)CFS patients support the reports of retrovirus infections.

“Recently, DNA from a human gammaretrovirus, xenotropic murine leukaemia virus-related virus (XMRV) was found in the PBMC of 68 of 101 patients compared to 8 of 218 healthy controls. Patient–derived, activated PBMC produced infectious XMRV in vitro. Both cell associated and cell-free transmission of the virus to uninfected primary lymphocytes and indicator cell lines was possible.

“The decreased natural killer (NK) cell cytotoxic and lymphoproliferative activities and increased allergic and autoimmune manifestations in (ME)CFS would be compatible with the hypothesis that the immune system of affected individuals is biased towards a T-helper (TH) 2 type, or humoral immunity-orientated cytokine pattern.

“The elevations in LTa, IL-1a, IL1b and IL-6 indicate inflammation, likely to be accompanied by autoantibody production, inappropriate fatigue, myalgia and arthralgia, as well as changes in mood and sleep patterns.

“This study is among the first in the (ME)CFS literature to report the plasma profiles of a reasonably large panel of cytokines assessed simultaneously by multiplex technique.

“Cytokine abnormalities appear to be common in (ME)CFS. The changes from the normal position indicate immune activation and inflammation.

“The results imply a disorganised regulatory pattern of TH1 function, critical to antiviral defence.

“The results from this study support a TH2 shift, pro-inflammatory cytokine up-regulation and down-regulation of important mediators of cytotoxic cell function”.

Since it is now unequivocal that people with (ME)CFS show markers of inflammation, what will be the impact on the Wessely School’s MRC PACE Trial that is predicated on the assumptions of deconditioning, on the “perception” of effort and on aberrant illness beliefs and whose participants are instructed about “sleep hygiene”?

Two responses around XMRV: Prof Simon Wessely; Dept of Health

Two responses around XMRV: Prof Simon Wessely; Dept of Health

Shortlink: http://wp.me/p5foE-2mS

Two users of the Whittemore Peterson Institute Facebook site have kindly given permission for the following responses to be reproduced here, on ME agenda.

Update: The response from Professor Simon Wessely following an enquiry by a member of the public has been removed since permission for publication and the terms under which Professor Wessely’s response might be republished had not been discussed.  A copy of the response was also published by me via Co-Cure together with the response from the Department of Health.  This is also being removed.

——————-

Whittemore Peterson Institute on Facebook

Heath reported on 12 November that he wrote to the Department of Health.  The DoH response was:

Thank you for your email of 28 October to the Department of Health about xenotropic murine leukemia virus-related virus and chronic fatigue syndrome/myalgic encephalopathy (CFS/ME).

The Department of Health agrees with the World Health Organization’s classification of CFS/ME as a neurological condition of unknown cause. The Department also agrees that CFS/ME is a genuine and disabling illness and can have a profound effect on those living with the condition. That is why research breakthroughs such as the one outlined in your email, are so important to developing the knowledge base.

The National Institute for Health and Clinical Excellence (NICE) clinical guidelines are updated as needed so that recommendations take into account important new evidence. However, as I hope you will appreciate, as NICE is an independent body, the time-frame for revising guidance and the evidence it uses are matters entirely for NICE. You may therefore wish to raise this issue directly with NICE’s Chief Executive, Andrew Dillon, at the following address:

NICE
MidCity Place
71 High Holborn
London WC1V 6NA

I think it also helpful to emphasise that NICE clinical guidelines are just that – guidelines for healthcare professionals use in conjunction with their clinical judgement and based on an individual assessment of each patient’s needs. The guideline recognises that there is no one form of treatment to suit every patient and it does not force patients into treatments they do not want.

The guideline emphasises a collaborative relationship between clinician and patient, that treatment and care should take into account personal needs and preferences, and that healthcare professionals should recognise that the person with CFS/ME is in charge of the aims of the treatment programme.

Cognitive Behavioural Therapy is a rehabilitative approach designed to modify the way patients think and behave about their illness and so improve physical symptoms. In common with other illnesses and conditions where it has been successfully used such as chronic pain, cancer, heart disease and diabetes, its use does not imply that the cause of the illness is psychological.

The Department feels that it is not helpful to differentiate between biomedical and psychosocial treatments as, based on clinical evidence that is currently available, patients are best served by a holistic approach.

You also comment on the paucity of bio-medical research. I know that many of the Department’s stakeholders see biomedical research as the key to developing new treatments and the Department appreciates the concern about a lack of biomedical research in this area.

As you may know, the main agency through which the Government supports medical and clinical research is the Medical Research Council (MRC). The MRC is wholly independent in its choice of which research to support and it does not generally earmark funds for particular topics. It maintains a rigorous decision making process and only funds research that is likely to make a significant contribution to knowledge and is a good use of taxpayers’ money. Decisions to support proposals are taken on the grounds of scientific quality and whether the research proposed would be likely to inform the knowledge base. There is certainly no bias, and the Department knows that the MRC remains committed to funding scientific research in all aspects of CFS/ME.

The Department understands that the MRC continues to attract a small number of proposals for biomedical research. The problem is that there appears to be a shortage of good and innovative ideas within the scientific community itself. This is something the Department knows that the CFS/ME community and the MRC are aware of, and the MRC have endeavoured to address this by engaging with patient groups to encourage high quality research proposals. The MRC continues to acknowledge the importance of research into CFS/ME, and it is difficult to see what more the MRC could do without lowering the quality threshold.

I hope this reply is helpful.

Yours sincerely,

Priya Bassan
Department of Health

Related information:

Source: ME Research UK

http://www.meresearch.org.uk/information/publications/casetoanswer.html

The Medical Research Council: a case to answer?

[...]

CFS/ME projects currently funded by the MRC
(Sources: MRC website; Hansard, written answers)

•Two large clinical trials of new approaches to treating CFS/ME:
          PACE (Pacing, Activity and Cognitive Behaviour Therapy: a Randomised Evaluation, £2,076,363) [Prof. PD White, Psychological Medicine, Queen Mary and Westfield College]
          FINE (Fatigue Intervention by Nurses Evaluation, £824,129) [Dr AJ Wearden, Psychological Science, Uni. of Manchester]

•A preliminary epidemiological project to test the feasibility of identifying the risk factors for persistent symptoms of fatigue and abdominal and widespread pain (£118,263) [Prof. F Creed, Psychological Medicine, University of Manchester]

•An epidemiological study to assess ethnic variations of the prevalence of a CFS-like illness, associations with potential risk factors, and coping behaviours (£162,145) [Prof. K Bhui, Cultural Psychiatry and Epidemiolgy, Queen Mary and Westfield College]

•Indirect support through a trial exploring the management of patients with persistent unexplained symptoms [Specifics unknown]

•One project was mentioned in Hansard (12th June 2008) but is not on the MRC website: General and specific risk markers and preventive factors for chronic fatigue and irritable bowel syndromes (£367,000) [Dr C Clark, Centre for Psychiatry, Barts and The London School of Medicine]

 

Table. Unfunded applications to the MRC between 2002 and 2008

Time-frame   (number of applications)   CFS/ME subject area

2002 to 2005 (11 total) Neurophysiology of fatigue; Population-based/epidemiological studies (4 applications); Neurotransmitters and stress; Neuroimaging; Clinical and laboratory characterisation physiology/diagnosis); Dietary intervention — RCT; Facilitated self-help — RCT; Psychosocial and genetic factors in young people

2005 to 2006 (12 total) Pathophysiology, including studies regarding genetics/biomarkers, immunology and neuroimaging (7 applications); Population-based/epidemiological studies (3); Primary care study; Experimental medicine study

2006 to April 2007 (7 total) Cognitive outcomes in children — pathophysiology; Epidemiological studies — epidemiology; Biomarkers; Pathophysiology (2 applications); Molecular pathogenesis — pathophysiology; Molecular and genetic characterisation — pathophysiology; Neuroimaging — pathophysiology

May 2007 to June 2008 (3 total) Biomarkers — pathophysiology; Management and treatment — intervention; Management and treatment — observational study

XMRV Retrovirus: Round up 19: XMRV Blood Safety and Availability from HHS (US), PhD study

XMRV Retrovirus Whittemore Peterson Institute Science Mikovits Chronic Fatigue Syndrome

XMRV Retrovirus: Round up 19: XMRV Blood Safety and Availability from HHS (US), PhD study

WordPress Shortlink: http://wp.me/p5foE-2gR

 

For initial Whittemore Peterson Press Release, NIH (National Institutes of Health) News Release, Science paper go here: http://wp.me/p5foE-272

Click here for all previous XMRV Round ups and postings in reverse date order:

http://meagenda.wordpress.com/category/xmrv/

—————-

XMRV Blood Safety and Availability from HHS (US)

On the CFIDS Association site

http://www.facebook.com/CFIDSAssn#/CFIDSAssn?v=app_2347471856

Xenotropic Murine LeukemiaVirus-Related Virus (XMRV)
Blood Safety and Availability
Office of Public Health and Science
Department of Health and Human Services (HHS)Jerry A. Holmberg, PhD, SBB
October 30, 200930 October 2009

The Office of Public Health and Science’s Blood Safety and Availability is aware of the recent literature suggesting linkage of chronic fatigue syndrome to a possible contagious rodent retrovirus, XMRV. XMRV has also been associated with an aggressive form of prostate cancer. Antibodies against the virus have been detected in 3.7% of healthy controls in a study of a small number of individuals. Currently there is no commercially available test for infection with XMRV. While there is no known association of CFS or prostate cancer with history of transfusion, the finding that the virus is associated with white blood cells has led some to question whether XMRV could be transmitted by transfusion and might therefore pose a threat to the health of blood recipients and potentially also transplant recipients.

The HHS Blood Safety Committee works with all the PHS agencies (i.e., CDC, FDA, HRSA, and NIH) to ensure the safety and availability of blood products as well as transplantation safety. Under the leadership of that committee, steps are being taken to investigate the blood safety threat from XMRV and the potentially protective role of white cell removal, which is performed on approximately 70% of blood. An interagency Emerging Infectious Diseases working group that reports to the Blood Safety Committee is currently assessing the literature on XMRV, conducting meetings with experts on this retrovirus, and interacting with groups that could study the question of blood safety. A report is expected within several weeks. In particular, the National Heart Lung and Blood Institute Retrovirus Epidemiology Donor Study-II (REDS-II) investigators are aware of the report in Science and are assessing the prevalence of XMRV in blood donors to determine whether studies aimed at evaluating transfusion-transmission rate are warranted using NHLBI’s repositories of donor and recipient blood samples.

HHS will remain vigilant in assessing the safety of the blood supply and developing interventions as appropriate.

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

Links to Other Federal Guidelines

National Cancer Institute Interim Guidelines on XMRV:
http://www.cfids.org/temp/xmrv-guidelines-nci.asp 

NIH Fact Sheet on Transfusion Safety (general): http://www.nih.gov/about/researchresultsforthepublic/Transfusion.pdf

—————-

PhD Project, University College London

PDF here

http://www.findaphd.com/search/showproject.asp?projectid=18971  

Dept/SchoolDivision of Infection & Immunity, University College London
Project Supervisor(s) Prof G Towers Dr P Kellam

Funding Availability Competition Funded Project (European/UK Students Only)

Application Deadline 23 November 2009

A role for XMRV in human disease

Laboratory supervisor: Prof Greg Towers

Clinical supervisor: Prof Deenan Pillay

Xenotropic murine retrovirus (XMRV) has recently been associated with chronic fatigue syndrome as well as prostate carcinoma in humans (1-3). XMRV is a murine endogenous virus found in the genome of mice and until recently has been thought to be absent from the human population. It is now becoming clear that XMRV has transmitted to humans by a process of zoonosis, presumably from mice, and appears to be associated with a variety of diseases not previously associated with viral infection.

1. We will establish quantitative PCR assays and serology assays including enzyme linked immunosorbant assays (ELISA) to detect and quantify XMRV. Importantly, assays used to detect related murine leukaemia viruses in the lab are expected to be suitable.

2. We will use these assays to measure XMRV load in chronic fatigue patient samples as well as, well but XMRV infected control samples, with a view to establishing whether viral load relates to disease, episodes of illness and/or severity.

3. The receptor for XMRV has been identified. We will seek human polymorphism in the xenotropic receptor and assess which human cells express it. We will also establish which cells in vivo in blood express the receptor and which cells are infected with XMRV by quantitative PCR on sorted subsets of B and T cells from XMRV infected individuals.

This project proposes to address some of the most important questions surrounding the recently described XMRV infection of humans and to seek a therapeutic strategy for XMRV treatment. We expect it to be a competitive project and the experiments performed are likely to be influenced by ongoing studies published as we go. We expect that the candidate will be fully trained in modern techniques of molecular virology during the course of this project.

TO APPLY Send THREE COPIES of your CV (including full contact details of two academic referees) a personal statement and an indication of your top two preferences, on a separate page, from the list of projects below to:

Isabel Lubeiro, Division of Infection & Immunity, Windeyer Building, 46 Cleveland Street, London W1T 4JF.
CLOSING DATE: 23 NOVEMBER 2009

—————-

Media

From Dr Marc-Alexander Fluks via Co-Cure

Source: Irish Medical Times
Date: October 29, 2009
Author: Garrett FitzGerald
URL: http://www.imt.ie/opinion/2009/10/retrovirus_may_shed_light_on_m.html

Retrovirus may shed light on mystery of chronic fatigue

Back in the news big-time is Chronic Fatigue Syndrome. A recent paper in Science reports infection with a gammaretrovirus (XMRV) in 67 per cent of cases. The virus has been detected from blood and saliva in long-term sufferers.

Is it time to apologise to all the patients who were diagnosed as being somewhat cracked? I recall one colleague referring to the condition as the Muirisheen Durkan syndrome: So, goodbye Muirisheen Durkan I’m sick and tired of workin’!

For some unknown reason, I was sent many patients with the syndrome from all over the country. I was almost always impressed by the genuine nature of the symptoms, having no doubt that there just had to be something other than psychological reasons underneath.

I could do nothing for them

I listened (often the consultation lasted more than an hour) and in most instances after investigation told the patients that they were probably suffering from CFS/ME. I told them I could do nothing for them in terms of cure or alleviation. The only contribution I made was to warn them about the quacks which they (understandably) were attending or about to attend.

One patient was attending a great man in London, who claimed he was a physician to the Queen (lucky ol’ Queen), who kept admitting the patient to private hospitals over there for infusions of vitamins and Lord knows what else.

There was no improvement, surprisingly, in a well-nourished, fruit- eating young female whose gums were not bleeding onto the tablecloth. He would tell her that she hadn’t had enough courses of the infusions just yet, to stick with them. The patient had sold her house and was in the process of selling her car to pay the fees for this Hippocratic artiste.

Money-mad mountebanks

My intervention did nothing for the symptoms, but the patient got to hold on to her car. Many fell into the clutches of money-mad mountebanks, chancers, crystal-ball gazers and three-card-trick merchants. Regrettably, most of these were practicing medical doctors.

Some patients who had previously been leading a fully active and productive life were reduced to being little better than bed-ridden. The Royal College of Psychiatrists classified the condition as (partly) a psychiatric illness about 20 years ago and recommended courses of psychotherapy.

In earlier papers, there was some response to the sessions, most patients saying that they were a little better.

Some of my patients were depressed. Their symptoms sometimes responded to SSRIs, but they were left with their original degree of fatigue unchanged. Some patients seemed to remit spontaneously after anything from two to 20 years after the onset of the condition.

Accepted the diagnoses

A rare patient improved substantially with psychiatrist-prescribed Prozac in doses exceeding 80mg/day. Most did not improve. In fairness, both the Departments of Health and Social Welfare accepted the diagnoses of ME/Post-viral Syndrome/CFS as grounds for awarding disability benefits.

Specialists in Internal Medicine generally recommended a program which included increasing amounts of physical exercise. My own experience was that almost none of the patients could walk more than the length of themselves without ‘paying’ for it – having to recover in bed for two or three days.

The ME patients’ support group lobbied well for their members, but were despondent about the future. Many patients felt ridiculed (by the attitude of some professionals) and concealed the diagnosis. Many had by then lost their livelihoods and their own self-respect and self-worth.

One swallow does not a summer make. Before deciding that the retrovirus is actually causative, we await the outcome of further studies. If these are confirmatory, we wait for the results of trials of anti-retroviral therapy. As always, the thinking doctor will be cautious.

—————-

From Dr John Greensmith via Co-Cure

Letter link:

http://www.bexhillobserver.net/letters-to-the-editor/Your-letters–October-23.5761548.jp 

(Scroll down long way, 18 of 20 letters to “Beware Study”)

Title: Beware Study, Letters, Bexhill-on-Sea Observer, 23 October 2009

Text:

Further to the recent article about a research study carried out in America that suggests a link between a retrovirus and ME (Does a virus cause ME?, Bexhill Observer, 14 October 2009), after consulting with our medical advisers people with the illness should be aware that, while very interesting and encouraging, these findings do need to be replicated in other laboratories.

This is not the first time that a retrovirus has been suggested to play a major part in ME, and before it was sadly found to be a false dawn.

We also need to be aware that, even if an association is confirmed we don’t yet know if it is a cause or a consequence  of ME. It would be premature to think about tests and treatments until we know very much more.

On the other hand, this finding will encourage more biomedical research that will increase our understanding of ME. The message from our advisers is that although this is a very interesting advance, we should not get too excited about it until we know more.

There is much that can be done to help those with ME, as a survey run by our charity recently in the area shows.

For more information call 01273 674828 or see www.measussex.org.uk 

Colin Barton
Chairman
Sussex ME/CFS Society

—————-

CFSAC meeting Days One and Two

Videocasts of the entire proceedings will be available shortly from the NIH wesbite. I will post the links for these once these are online (RealPlayer required): http://videocast.nih.gov/PastEvents.asp

Dr David Bell’s presentation PowerPoint Slides can be viewed here:

http://www.hhs.gov/advcomcfs/meetings/agendas/bell_factitious_102909.ppt

 

YouTubes

Clips of Dr Dan Peterson’s presentation and Annette Whittemore: http://www.youtube.com/user/Khalyal

Also on this channel plus some patient testimonies: http://www.youtube.com/user/luminescentfeeling

—————-

Whittemore Peterson Website Q & A

http://www.wpinstitute.org/xmrv/xmrv_qa.html

—————-

CFIDS Association of America

Website: http://www.cfids.org/ 

On Facebook: http://www.facebook.com/CFIDSAssn

Facebook Notes page (includes notes on CFSAC meeting):

http://www.facebook.com/CFIDSAssn#/CFIDSAssn?v=app_2347471856

—————-

Patient community websites, blogs and forums

Cort Johnson’s website: http://aboutmecfs.org/Conf/IACFSME09WPI.aspx

The IACFS/ME Conference II: the Hit of the Conference
The Whittemore-Peterson Neuro-Immune Institute

Reno, Nevada: March 12-16, 2009

Forums: http://forums.aboutmecfs.org/index.php

—————-

The Definition Petition

Petition webpage: http://CFSdefinitionpetition.notlong.com
i.e. http://www.ipetitions.com/petition/empirical_defn_and_CFS_research

If you haven’t already signed it – sign the CFS Definition Petition today at: http://CFSdefinitionpetition.notlong.com

Dr Nigel Speight resigns from children and young person’s organisation AYME

Dr Nigel Speight resigns from the children and young person’s organisation AYME

For many years, paediatric specialist, Dr Nigel Speight, has been a champion of families with a child or young person with ME or where ME is suspected. 

He has advocated for families facing wrongful accusation of MSpB (FII), where child protection orders have been instigated or threatened following disagreements between the family and the child’s medical professionals over the management of the condition, where medical professionals have been unwilling to make a diagnosis of ME and where social services have become involved in the case when a child or young person has been unable to regularly attend mainstream school due to ill health.

Dr Speight recently announced his resignation as a Patron to the children and young person’s patient organisation, AYME [Association of Young People with ME]  http://www.ayme.org.uk/.

AYME’s Medical Advisor is Dr Esther Crawley, Consultant Paediatrician at the Royal National Hospital for Rheumatic Diseases NHS Foundation Trust. Dr Crawley had been a member of the NICE CFS/ME Guideline Development Group. 

Dr Speight, who is now retired from the NHS, has become a Medical Advisor to the 25% M.E. Group.

The following announcement was published in a recent 25% M.E. Group newsletter:

I just thought I should inform you officially that after a long and happy association with AYME I have decided to resign as their Patron. Without going into too much detail I would say that over the last couple of years I have become aware that they have changed their position on several areas and that our views have accordingly diverged. In particular AYME seem to have become more willing to collaborate with the medical and psychiatric establishment in order to appear respectable. This appears to have been the cause of AYME’s relative enthusiasm for the NICE Guidelines, which most of us feel involve an overemphasis on CBT and GET. This compromise seems to have helped the psychiatrists to get a new lease of life.

The result of all this is that AYME appear to have alienated themselves from most of the other ME charities (with the exception of AfME [Action for M.E.] who appear to be taking a similar position). In this controversy I feel more in sympathy with the rest of you. I have gained the impression that AYME no longer appreciate my opinions and prefer my status as their figurehead to be a largely silent one. It is a combination of all these factors that has caused me to resign and I am sure you will all understand.

With Best Wishes

Nigel Speight

Journal of Psychosomatic Research: In Press: Is there a better term than “Medically unexplained symptoms”?

Image | belgianchocolate | Creative Commons

Keywords

APA    DSM    DSM-IV    DSM-V    WHO    ICD    ICD-10    ICD-11    American Psychiatric Association    Diagnostic and Statistical Manual of Mental Disorders    World Health Organization    Classifications    DSM Revision Process    DSM-V Task Force    DSM-V Somatic Distress Disorders Work Group    Somatic Symptom Disorders Work Group    DSM-ICD Harmonization Coordination Group    International Advisory Group    Revision of ICD Mental and Behavioural Disorders    Global Scientific Partnership Coordination Group    ICD Update and Revision Platform    WHO Collaborating Centre    CISSD Project    MUPSS Project    Somatoform    Somatisation    Somatization    Functional Somatic Syndromes    FSS    MUS    Myalgic encephalomyelitis    ME    Chronic fatigue syndrome    CFS    Fibromyalgia    FM    IBS    CS    CI    GWS

The Elephant in the Room Series Three:

Journal of Psychosomatic Research In Press: Is there a better term than “Medically unexplained symptoms”?

WordPress Shortlink for this posting: http://wp.me/p5foE-2d6

24 October 2009

 

An In Press version of the Editorial: Is there a better term than “Medically unexplained symptoms”?, to be published in a forthcoming issue of the Journal of Psychosomatic Research, is already available online (purchase required). The Editorial needs to be read in conjunction with a white paper from:

The European Association for Consultation-Liaison Psychiatry and Psychosomatics (EACLPP) http://www.eaclpp.org/

A white paper of the EACLPP Medically Unexplained Symptoms study group

Patients with medically unexplained symptoms and somatisation – a challenge for European health care systems  (Gillian.D.Dunkerley@manchester.ac.uk )

The White Paper can be downloaded from the EACLPP site here: http://www.eaclpp.org/working_groups.html

The document is approx 76 pages long, including tables and charts.  I had considerable difficulty opening this document, in May, due to a corrupted table and I note that the file on the EACLPP site is still glitchy. A copy of the document was therefore obtained directly from the EACLPP and can be opened by clicking the link below.  Note that there may have been revisions to the document as supplied on 19 May, but it will serve as reference for those who might also experience difficulties opening the file from the EACLPP website. If you would like a copy of the file sent to you as a Word.doc, email ME agenda with “EACLPP MUS DOC” in the subject line and I will forward a copy [600 KB].  The tables and charts are slow to load.

Draft – prepared by: Peter Henningsen and Francis Creed January 2009

EACLPP Working group on MUS version 16 Jan 2009

The current issue of the Journal of Psychosomatic Research is Volume 67, Issue 5, Pages A1-A4, 367-466 (November 2009)  http://www.sciencedirect.com/science/journal/00223999

Journal of Psychosomatic Research

In Press

Editorial
Is there a better term than “Medically unexplained symptoms”?

Abstract: http://tinyurl.com/jpsychoresMUS

doi:10.1016/j.jpsychores.2009.09.004

References and further reading may be available for this article. To view references and further reading you must purchase this article.

Editorial

Francis Creed a, Elspeth Guthrie a, Per Fink b, Peter Henningsen c, Winfried Rief d, Michael Sharpe e and Peter White f

a University of Manchester, Manchester, UK 
b University Hospital Aarhus, Denmark
c Technical University, Munich Germany
d University of Marburg, Germany
e University of Edinburgh, UK
f Queen Mary University of London, UK

Received 24 August 2009; revised 24 August 2009; accepted 7 September 2009. Available online 17 October 2009.

Article Outline

Introduction

“Medically unexplained symptoms” – one advantage, but many reasons to discontinue use of the term

Criteria to judge the value of alternative terms for “medically unexplained symptoms”

Terms suggested as alternatives for “medically unexplained symptoms”

Implications for treatment

Implications for DSM-V and ICD-11

Conclusion

References

Note:

Francis Creed is Co-Editor of the Journal of Psychosomatic Research.

Francis Creed, Per Fink, Peter Henningsen and Winfried Rief were all members of the international CISSD Project, (Principal Administrators: Action for M.E.; Co-ordinator: Dr Richard Sykes. Dr Sykes is now engaged in the “London MUPSS Project” in association with the Institute of Psychiatry).

Michael Sharpe was UK Chair for the CISSD Project.

Michael Sharpe and Francis Creed have been members of the APA’s DSM-V Somatic Distress Disorders Work Group since 2007.

Francis Creed (UK), Peter Henningsen (Germany) and Per Fink (Denmark) are the co-ordinators of European EACLPP MUS Work Group.

Francis Creed and Peter Henningsen were the authors of “A white paper of the EACLPP Medically Unexplained Symptoms study group – Patients with medically unexplained symptoms and somatisation – a challenge for European health care systems”, January 2009.

Draft white paper here: http://www.eaclpp.org/working_groups.html

Per Fink is a member of the Danish Working Group on Chronic Fatigue Syndrome, established in August 2008 and expected to complete its work in spring 2009.

 

An Editorial: The proposed diagnosis of somatic symptom disorders in DSM-V to replace somatoform disorders in DSM-IV – a preliminary report by DSM-V Work Group members, Joel Dimsdale and Francis Creed on behalf of the DSM-V Workgroup on Somatic Symptom Disorders was published in the June 2009 issue of the Journal of Psychosomatic Research.

Full text of the June 2009 DSM-V SSD Work Group preliminary report can be accessed here:

http://www.jpsychores.com/article/S0022-3999(09)00088-9/fulltext

See section: Psychological factor affecting general medical condition 

“…The conceptual framework that we propose will allow a diagnosis of somatic symptom disorder in addition to a general medical condition, whether the latter is a well-recognized organic disease or a functional somatic syndrome such as irritable bowel syndrome or chronic fatigue syndrome…”

No updates or reports have been published on the APA’s website by DSM-V Task Force or Work Groups since brief reports issued in April 2009. DSM-V is anticipated to be finalised in May 2012 with field trials expected to start this October. No detailed Timeline for DSM-V is available.

Previous DSM Task Force chairs, Robert L Spitzer and Allen Frances, have been two of the most vocal critics of the current Task Force’s oversight of the revision process. Read their joint letter to the APA Board of Trustees here:  Letter to APA Board of Trustees July 09. In Dr Frances Responds to Dr Carpenter: A Sharp Difference of Opinion, Psychiatric Times, 9 July, Frances called for the posting of all the suggested wordings for DSM-V criteria sets well before considering field trials.

 

Javier Escobar, co-author of the Special Report: Unexplained Physical Symptoms: What’s a Psychiatrist to Do? Psychiatric Times, Aug 2008, was also a member of the Work Group for the “Conceptual Issues in Somatoform and Similar Disorders (CISSD) Project.

Javier Escobar is a member of the DSM-V Task Force, serves as a Task Force liaison to the Somatic Symptom Disorders Work Group and said to work closely with this work group.

http://www.psychiatrictimes.com/display/article/10168/1171223

01 August 2008
Psychiatric Times. Vol. 25 No. 9
Special Report

PSYCHIATRY AND MEDICAL ILLNESS
Unexplained Physical Symptoms What’s a Psychiatrist to Do?

Humberto Marin, MD and Javier I. Escobar, MD

According to Escobar and Marin:

“The list of somatoform disorders kept expanding with the addition of vague categories, such as “undifferentiated somatoform disorder” or “somatoform disorder NOS [not otherwise specified],” which, unfortunately, are the most common diagnoses within the somatoform genre. These terms failed to transcend specialty boundaries. Perhaps as a corollary of turf issues, general medicine and medical specialties started carving these syndromes with their own tools. The resulting list of “medicalized,” specialty-driven labels that continues to expand includes fibromyalgia, chronic fatigue syndome, multiple chemical sensitivity, and many others (Table 1).

Table 1

Functional somatic syndromes

Irritable bowel syndrome
Chronic fatigue syndrome
Fibromyalgia
Multiple chemical sensitivity
Nonspecific chest pain
Premenstrual disorder
Non-ulcer dyspepsia
Repetitive strain injury
Tension headache
Temporomandibular joint disorder
Atypical facial pain
Hyperventilation syndrome
Globus syndrome
Sick building syndrome
Chronic pelvic pain
Chronic whiplash syndrome
Chronic Lyme disease
Silicone breast implant effects
Candidiasis hypersensivity
Food allergy
Gulf War syndrome
Mitral valve prolapse
Hypoglycemia
Chronic low back pain
Dizziness
Interstitial cystitis
Tinnitus
Pseudoseizures
Insomnia
Systemic yeast infection
Total allergy syndrome”

These labels fall under the general category of functional somatic syndromes and seem more acceptable to patients because they may be perceived as less stigmatizing than psychiatric ones. However, using DSM criteria, virtually all these functional syndromes would fall into the somatoform disorders category given their phenomenology, unknown physical causes, absence of reliable markers, and the frequent coexistence of somatic and psychiatric symptoms.”

DSM-V and ICD-11 have committed as far as possible “to facilitate the achievement of the highest possible extent of uniformity and harmonization between ICD-11 mental and behavioural disorders and DSM-V disorders and their diagnostic criteria” with the objective that “the WHO and APA should make all attempts to ensure that in their core versions, the category names, glossary descriptions and criteria are identical for ICD and DSM.”

The International Advisory Group for the Revision of ICD-10 Mental and Behavioural Disorders most recent meeting took place on 28 – 29 September. It is anticipated that a Summary Report of the meeting will be available in late November/December.

For detailed information on the proposed structure of ICD-11, the Content Model and operation of iCAT, the collaborative authoring platform through which the WHO will be revising ICD-10, please scrutinise key documents on the ICD-11 Revision Google site:

https://sites.google.com/site/icd11revision/
https://sites.google.com/site/icd11revision/home/documents

For information around the DSM and ICD revision processes see DSM-V and ICD-11 Directory page: http://meagenda.wordpress.com/dsm-v-directory/

Observer: Flagship mental health scheme faces cutbacks 04.10.09

On Sunday, the Observer reported on cutbacks faced by Improving Access to Psychological Therapies (Iapt) programme which is failing to meet government tarkets:

The Observer | 4 October 2009

http://www.guardian.co.uk/society/2009/oct/04/mental-health-therapy-cbt-psychiatry

Flagship mental health scheme faces cutbacks

Only 400 therapists have been trained out of the 3,600 needed for the scheme

by Jamie Doward

“A flagship government strategy to train an army of therapists to get the nation off antidepressants and into work could be dramatically scaled back amid claims it is experiencing problems.”

The government claims the Improving Access to Psychological Therapies (Iapt) programme will treat 900,000 people and help about half of them to make a full recovery. It also aims to get 25,000 people suffering from anxiety and depression off sick pay and benefits by 2010/11.

But the Observer understands there are now concerns about whether these targets can be met.”

Read full article here

————————-

Related material

Tories would force jobless to work  |  Sunday Times  |  4 October 2009
http://www.timesonline.co.uk/tol/news/politics/article6860233.ece

Cameron to slash benefit payouts to 500,000 now deemed ‘unfit to work’  |  Times |  5 October 2009 http://www.timesonline.co.uk/tol/news/politics/article6861137.ece 

Iapt documents: http://www.iapt.nhs.uk/publications/

See also: The Elephant in the Room Series Two: More on MUPS

See also: Lords Debate on CBT

Interstitial cystitis and Chronic Fatigue Syndrome: Margaret Williams 26.08.09

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

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

Interstitial cystitis and Chronic Fatigue Syndrome

Margaret Williams

26 August 2009

That there is a concerted campaign by members of the Wessely School to re-classify as a single somatoform disorder various disparate syndromes whose aetiology remains undetermined cannot be disputed.

It is worth noting that the British Medical Journal recently carried a well-structured Clinical Review of interstitial cystitis, a condition associated with gross bladder wall changes, and painful bladder syndrome, which exhibits the same symptoms but lacks gross cystoscopic findings (Serge Marinkovic et al; BMJ 8th August 2009:339:337-342). The authors stated that patients with IC are 100 times more likely to have irritable bowel syndrome and are 30 times more likely to have systemic lupus erythematosus, and that other associated chronic illnesses include fibromyalgia and chronic fatigue syndrome. The authors provided a compelling but unconfirmed theory – based on evidence that the authors say represents the majority opinion of researchers actively involved in the field – of likely autoimmune causation:

“The pathological features of bladder epithelial damage and related blood vessel transitions in the absence of infection have been recognised for more than 100 years… One theory is that increased permeability of the protective glycosaminoglycan lining of the bladder epithelium causes potassium (and) toxins to leak into the mucosal interstitium, activating mast cells and generating an autoimmune response. Mast cells produce immune reactive chemicals, which in turn cause generalised bladder inflammation and bladder mucosal damage through the presence of tachykinins and cytokines. These further mediate the release of histamine, tumour necrosis factor, chymase, tryptase, and prostaglandins. Finally, inflammatory agents sensitise bladder neurones, producing pelvic and bladder pain…..Some patients have exacerbations of their symptoms after ingesting certain food or dinks….Urothelial cell cultures express abnormal gene variants. When urothelial biopsies…were subjected to stretch…they released significantly higher concentrations of ATP than control biopsies, suggesting that ATP plays an important role in this syndrome. An investigation of cultured bladder urothelial cells…showed that such cells had higher than normal concentrations of ATP, which decreases the ability of the bladder wall to conduct potassium ions…which again indicates that impaired potassium conduction is involved in the pathophysiology of interstitial cystitis”.

Professor Simon Wessely, champion of cognitive behavioural therapy and proponent of the psychosocial model of ME/CFS, seems to reject outright any autoimmune or allergic component:

“The article…details associations with fibromyalgia, chronic fatigue syndrome and, strikingly, a 100-fold increased risk of irritable bowel syndrome – all of which have good evidence for the role, at least in part, of psychological factors in the their aetiology or maintenance…It is highly possible that psychological factors have an aetiological contribution to conditions such as painful bladder syndrome. Such disorders, where physical pathology cannot fully account for symptoms, are known as ‘medically unexplained’ or ‘functional’ (somatic) syndromes…It has been proposed (citing his own Lancet paper 1999:354:936-939) that they may be the same underlying disorder manifesting itself in different bodily systems…Dr Marinkovic, however, despite drawing out the evidence for such a description, seems to resist the inference, making no mention of psychological factors even as possible contributors to the aetiology…The experience of other functional somatic syndromes…is that a biopsychosocial approach is the foundation of successful cognitive behavioural therapy. This…surely deserves a place in any review (of) painful bladder syndrome”.

http://www.bmj.com/cgi/eletters/339/jul31_2/b2707#218935

People must decide for themselves whether or not, based on the evidence, Dr Marinkovic did “draw out the evidence” that IC is a functional somatic disorder, and which of the two theories is the more convincing.

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Related items:

http://www.bmj.com/cgi/content/extract/339/jul31_2/b2707  

Published 31 July 2009, doi:10.1136/bmj.b2707
Cite this as: BMJ 2009;339:b2707

Clinical Review
The management of interstitial cystitis or painful bladder syndrome in women

Serge P Marinkovic, female reconstructive surgeon and women’s medicine specialist1, Robert Moldwin, associate professor of urology2, Lisa M Gillen, urology research associate3, Stuart L Stanton, professor emeritus of urogynecology and reconstructive surgery4

1 St Francis Hospital, 5255 Stop 11 Road, Indianapolis, IN 46259, USA, 2 The Arthur Smith Institute for Urology, Long Island Jewish Medical Center, 450 Lakeville Road, Suite M41, New Hyde Park, NY 11040, USA, 3 Division of Urology, Southern Illinois School of Medicine, Springfield, IL 62794, 4 St George’s Hospital, Tooting, London SW17 0QT

Read all BMJ Rapid Responses to this Clinical Review:

http://www.bmj.com/cgi/eletters/339/jul31_2/b2707#218312

 

UroToday.com

Developmental Influences On Medically Unexplained Symptoms

http://www.medicalnewstoday.com/articles/147575.php

25 Apr 2009

UroToday.com – Medically unexplained (functional) symptoms (MUS) are described as ‘physical symptoms that prompt the sufferer to seek healthcare but remain unexplained after an appropriate evaluation. They may affect as many as one third of people seeking medical care. In a provocative article, Tony Buffington of Columbus, Ohio suggests that BPS/IC and feline interstitial cystitis may be manifestations of MUS, and categorizing these conditions in that way may explain many findings that have been difficult to account for. In essence, he advances the migration  from an organ specific disease to a pain syndrome one step further.

Read full article

Times Letters: British intervention in healthcare debate in the US and our NHS

In response to the report “David Cameron turns on MEP Daniel Hannan for anti-NHS tour in America” Times Online, 14 August,  H Patten has a letter published today in the print and online editions:

Times Letters

http://www.timesonline.co.uk/tol/comment/letters/article6798223.ece

The Times
August 17, 2009

‘Untruths’ about NHS system of healthcare
British intervention in the healthcare debate in the US and our NHS

Sir, The quarter of a million sufferers of myalgic encephalomyelitis (ME) in this country, who can access no effective NHS treatment for their physical illness, might agree with Mr Hannan in that they would not wish their NHS “care” on anybody.

ME has been classified as a physical, neurological illness (alongside MS and Parkinson’s) by the World Health Organisation since 1969. Instead of receiving biomedical treatment, ME sufferers are mixed up with sufferers of other fatigue-causing conditions, including mental ones, under the meaningless umbrella term “chronic fatigue syndrome”. In the UK no other neurological illness is treated solely by psychological interventions.

All UK taxpayers’ research and treatment millions have gone to the psychiatric profession that insist, against all scientific evidence, that it is an “abnormal illness belief”. No funding has ever been allotted to developing a diagnostic test. The parliamentary Gibson report recommended that these psychiatrists be investigated for a possible conflict of interest in also working for large insurance companies. This has never been done. Is healthcare here also, in President Obama’s words, “working better for the insurance companies” than for ME sufferers?

H. Patten

Frome, Somerset