ME Essential supplement, Spring 2014

ME Essential ONLINE SUPPLEMENT SPRING 2014

BRIDGE OVER TROUBLED WATER An account of the 2014 IACFS/ME Conference

by Dr Charles Shepherd, medical adviser to The ME Association (UK)

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AUTHOR’S FORWORD

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Contents PRESIDENT’S ROUNDUP

Big news, big numbers, super venue

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FIRST DAY

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FIRST DAY

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SECOND DAY

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‘San Francisco – we had a very busy four days’

Montoya and Lipkin set the scene Maxing the VO2 max test & orthostatic intolerance Autoimmunity, allergy and infection THIRD DAY

Leonard Jason stacks the case definition cards THIRD DAY

Exercise workouts or just plain provocation?

FINAL DAY

Rowe-ing the boat on children’s research FINAL DAY

Exciting new evidence of neuro-inflammation

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FINAL DAY

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FINAL DAY

The new IACFS/ME primer and closing thoughts by Professor Komaroff

DR CHARLES SHEPHERD reports on the 11th International Association for CFS/ME (IACFS/ME) conference that took place between Thursday March 20th and Sunday March 23rd at the Parc 55 Wyndham Hotel – right in the heart of San Francisco.

The event brought together an international group of researchers, clinicians and people with ME/CFS – the first day involving a patient conference running in parallel with a series of management-based workshops for health professionals.

With 50 research presentations,15 workshops, several breakout sessions, nearly 80 poster presentations and over four full days with 8am starts, I am not going to try and summarise every single item.

Instead, I will concentrate on presentations and workshops that are relevant to practical patient management, along with results from the most interesting research studies.

I want to thank The ME Association for funding my visit to San Francisco to attend what was a most enjoyable and interesting meeting – along with the opportunity to meet and network with most of the key members of the international ME/CFS research community.

Editor: Tony Britton Cover photo: Sunrise, Golden Gate Bridge | Royce Blair, 123RF photo library The ME Association, also registered as the ME Society, is a campaigning national charity that provides information and support to an estimated 250,000 people in the UK, their families and carers.

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ME Essential Summer 2014

PRESIDENT’S ROUND-UP

A few words from PROFESSOR FRED FRIEDBERG, Stony Brook University and President of the IACFS/ME The big news is the success of our international conference in San Francisco.

We recorded just under 400 attendees, the best showing in the last 15 years. Certainly the attractive venue was a big plus.

Also, Jose Montoya's CFS/ME research meeting at Stanford University Medical Center the day prior to the conference helped to boost our numbers (and vice versa).

The opening page of the conference programme

We also had a strong speaker schedule, including virologist Ian Lipkin, best-selling author Abraham Verghese (professor of medicine at Stanford), and Noel Rose, pioneering immunologist from John Hopkins University.

Much thanks to Jose and to board member Lily Chu for putting together the collaboration with Stanford.

Dan Peterson, as banquet keynote speaker, delivered an entertaining and informative history of the IACFS/ME. He also led an unusual and wellattended immunology workshop with 13 speakers.

Other first-time workshops included management of the severely ill patient (Chuck Lapp), paediatric CFS/ME (Katherine Rowe), and orthostatic intolerance (Peter Rowe).

In the research sessions, we saw more challenging studies in CFS/ME (exercise, cognitive challenge) that are intended to provoke biological abnormalities.

Also notable were studies conducted in the patient's home environment (eg, cytokines related to daily fatigue ratings).

The conference was held here – at the Parc 55 Wyndham Hotel ONLINE SUPPLEMENT

I view these as positive developments as they reflect new thinking in the field about how to identify abnormalities.

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FIRST DAY

On cytokines, inflammation and dedicated research at Stanford The conference was opened by Professor Fred Friedberg, President of the IACFS/ME. In the first address, Professor

Jose Montoya (pictured right)

spoke about the ME/CFS research initiative at California’s Stanford University School of Medicine,where a one-day conference was held the previous day. This is aimed at setting up a new Centre of Excellence involving researchers from anaesthetics, cardiovascular medicine, genetics, infection (with close collaboration with Professor Ian Lipkin), immunity, and neuroradiology. The Stanford study on inflammation involves 197 people with ME/CFS and 394 age- and sexmatched controls.

Professor Montoya briefed on some of the studies in progress, including one looking at how levels of immunesystem chemicals called cytokines are linked to severity of symptoms.

Using samples from both the ME/

CFS patients, and the healthy controls, the levels were measured of 51 different inflammation-associated chemicals – cytokine family/chemokines and hormones, including fat-cell produced hormones called adipokines.

Results indicate that 15 of these chemicals can distinguish cases of ME/CFS from controls, or correlate with symptom severity, or both. This is clearly very important news from the point of view of finding biomarkers (diagnostic tests) for ME/CFS and sub-grouping people under the ME/ CFS umbrella.

CS note: Along with the UK ME Biobank, this means we now have a growing number of databases with comprehensive clinical information and biosample banks containing blood, spinal fluid and other material/tissues that are vital for research purposes.

A quote here from Professor Tony Komaroff’s conference summary: Jared Younger and Dr. Montoya’s Center did a study that linked – tried to look for associations between the various cytokines being measured. The startling result, at least to me, was the primacy of Leptin.

Leptin is a hormone discovered about 1994 that is made by fat cells and diminishes appetite.

It has a powerful role in weight regulation and appetite control in humans and animals.

That this molecule should be so closely tied to immune system molecules, cytokines, was striking, and that it should so predominantly correlate with the levels of fatigue in the CFS patients was a novel insight, the meaning of which I’m sure many groups will be pursuing.

Inspiration from the virus-hunter Professor Ian Lipkin, who is Director of the Centre for Immunity and Infection at Columbia University in New York (pictured right), gave the opening keynote speech.

He took us on a fascinating tour of new and emerging infections, not just viruses, that cause human and animal disease – as well as those that may be involved in the pathogenesis of ME/CFS. Professor LIpkin spoke about the role of immune dysfunction, proinflammatory cytokines in the blood and spinal fluid particular, and his new research on the human microbiome – the population of

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more than 100 trillion micro-organisms that live in our gut, mouth, skin and elsewhere in our bodies.

These microbial communities have numerous beneficial functions that support life. They digest food, prevent disease-causing bacteria from invading the body, and synthesise essential nutrients and vitamins.

At the same time it was great to know that The ME Association appeal to raise a little over £3,000 for Professor Lipkin to come to Britain to speak at the UK Research Collaborative conference at the beginning of September had reached its target.

This was followed by two half-day

workshops aimed at clinical assessment and management rather than research developments. I went to the morning session on activity management, led by Staci Stevens, Christopher Snell, Mark VanNess and Todd Davenport (University of the Pacific).

The afternoon session was led

by Professor Peter Rowe (John Hopkins University School of Medicine, Baltimore) and covered orthostatic intolerance.

ME Essential Summer 2014

FIRST DAY

EXERCISE INTOLERANCE AND ACTIVITY MANAGEMENT WORKSHOP Post-exertional malaise (PEM) and symptom exacerbation are the defining characteristics of ME/CFS and the most difficult aspects to manage.

In order to identify the cardiac/heart, pulmonary/respiratory, metabolic and work-related abnormalities that contribute to PEM, the University of the Pacific research group has developed a protocol using noninvasive cardiopulmonary exercise testing (CPET). The computerised measurements of cardiopulmonary (= heart and lung) function during the 10- minute exercise test are made on two separate occasions over two days.

As a result, this group has helped to identify key pathophysiological changes that occur during exercise in people with ME/CFS – including an aerobic/oxygen system requiring impairment; autonomic nervous system dysfunction and immune system dysfunction – and how these abnormalities may relate to an inability in people with ME/CFS to carry out prolonged or repeated physical activity.

‘A single VO2 max test is not going to identify the Post Exertional Malaise’ The cardiopulmonary test-retest protocol – often referred to as the VO2 max test – used to identify and quantify PEM is not only useful in relation to clinical assessment and diagnosis of ME/CFS. It can also help with planning an activity programme that is matched to individual needs. However, it is important to note that a single exercise test is not going to produce the relevant information.

It is the second test that identifies PEM. The group also presented data to show that these abnormalities are not consistent with deconditioning – as some doctors still believe.

Using case study examples, the workshop considered practical aspects of activity management in ME/CFS. Key ‘take home’ messages included: l The use of heart-rate monitoring to help guide patients as to when to increase or decrease their activity levels.

l The importance of correct (ie diaphragmatic) breathing which helps to increase tissue oxygen- ation and reduce stress levels.

Many people with ME/CFS breathe shallowly and are only partially filling their lungs. To check you are breathing properly, lie down on the floor and breathe in through the nose for three seconds using the diaphragm (base of the chest – not the abdomen) and hold. Then breathe out through pursed lips.

‘This workshop was one of my conference highlights’

ORTHOSTATIC INTOLERANCE WORKSHOP

of ME/CFS provides an avenue for pragmatic and individual treatment.

The three-hour workshop led by PROFESSOR PETER ROWE on diagnosing and treating orthostatic intolerance/OI (where upright posture resulting in reduced blood flow to the brain aggravates ME/CFS symptoms) was one of my conference highlights. Along with numerous case histories, we covered cause, diagnosis and treatment of OI, orthostatic hypotension (= a significant fall in blood pressure on standing) and postural orthostatic tachycardia syndrome (POTS).

Symptoms of orthostatic intolerance include lightheadedness, fainting, reduced concentration, blurred vision, shortness of breath, chest discomfort, palpitations, feeling tremulous, nausea and nocturia (= passing urine at night). Physical signs can include a purplish discolouration to the skin on the feet and legs (= dependent acrocyanosis).

The key message was that recognition of these common components ONLINE SUPPLEMENT

Postural orthostatic tachycardia syndrome (POTS) occurs when orthostatic symptoms are linked to a 30-beats a minute rise in heart rate (40 beats a minute in adolescents), or a heart rate above 120, in the first

ten minutes of standing, or head-up tilt table testing – although this hospitalbased test may not contribute very much to confirming the diagnosis.

POTS is also more common in those with a joint hypermobility or pelvic congestion syndrome – the former being more common in young people with ME/CFS. Factors that increase the risk of orthostatic hypotension and POTS include prolonged sitting or standing, warm environments, sodium depletion, varicose veins, high carbohydrate meals (which divert blood to the intestines), alcohol and diuretics (water-losing drugs).

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FIRST DAY

From last page

ORTHOSTATIC INTOLERANCE Precipitating factors include pain, stress, exercise and hypoglycaemia (= low blood sugar).

Non-drug treatments include raising the head of the bed (to preserve blood volume at night), support hose/ stockings at 30-40 mm Hg pressure (waist/ thigh or knee high), body-shaper garments and abdominal binders (for more severe cases), drinking fluids every two hours (taking at least two litres a day), and adding a little salt to food. Helpful exercises include standing with legs crossed (to tense the calf muscles), squatting, leaning forward sitting and clenching fists when standing up.

Drugs used in the treatment of orthostatic hypotension include those which (a) increase the blood volume: sodium, which may be given intravenously in acute situations, fludrocortisone, clonidine, oral contraceptives, (b) decrease the release of chemicals called catecholamines: beta blockers and SSRIs and (c) drugs that constrict the size of the blood vessels: midrodone, SSRIs. This workshop also covered non-IgE mediated food allergy – caused by allergy to milk and soy proteins – and the use of vitamin B12 injections.

Symptoms, which are usually delayed by two to six hours following digestion, include fatigue, gastrointestinal symptoms (nausea, pain, early fullness), headaches and mouth ulcers.

Could this be an actual Immunology session chaired by Professor Nancy Klimas

Professor Noel Rose, Director,

Centre for Autoimmune Disease Research, John Hopkins University School of Medicine, started Friday morning with a comprehensive presentation on How do we recognise an autoimmune disease?

This is a subject that is becoming increasingly topical in ME/CFS in relation to the use Rituximab – a drug which may be an effective form of treatment in ME/CFS through its action on a part of the immune system that is involved in autoimmunity.

Professor Rose explained how there

He then summarised three types of evidence – direct, indirect and circumstantial – that are used to decide, with varying degrees of certainty, if a condition should be categorised as an autoimmune disease.

Direct evidence is the most persuasive form of evidence. This would

When allergy, immunology an

Other immunological presentations came from:

Dr Susan Levine, Cornell University, New York, on the link between allergic diseases and ME/CFS and whether some people have a unique immune signature/ phenotype that makes them more likely to develop allergies.

On the topic of vitamin B12 therapy, Professor Rowe cited a study that found depleted levels in the cerebrospinal fluid to justify the use of a trial of weekly injections of hydroxycobalamin 1000 microgramms for six weeks.

Among the more important laboratory findings in this study, which forms part of the Chronic Fatigue Initiative, were elevated levels of what are called allergy-associated cytokines and chemokines (ie IL-4, 6, 8, 10, 17A and CCL5 – an eosinophil-recruiting chemokine) and other pro-inflammatory cytokines in patients who had been ill for less than three years in comparison to those who had been ill for more than three years.

K The MEA has a leaflet on orthostatic intolerance, orthostatic hypotension and POTS. I will update i t to include what we learnt during this workshop.

The finding of elevated levels of molecules involved in allergic diathesis adds support to the hypothesis of a Th2 shift in ME/CFS. As Profes-

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are now around 80 conditions affecting a variety of body systems – blood, connective tissue, gastro-intestinal tract, hormonal and neurological etc – that are classified as autoimmune diseases. People who develop autoimmune diseases do so through a complex pathway that involves a genetic predisposition, environmental trigger factors such as infections, drugs, vaccinations and hormonal influences.

sor Tony Komaroff pointed out in his closing summary, these results suggest that the best place to look for immunological, and possibly other markers of disease activity, is in patients who are in the early stages of disease rather than later on.

Dr Ludovic Giloteaux, Cornell

University, New York, described a study that looked at plasma cytokine levels in patients and controls before and after a cardiopulmonary exercise test. After high intensity exercise, levels of the chemokine IP-10 decreased, indicating a degree of immune suppression.

Teilah Huth, Griffith University, Australia, presented further evidence of abnormalities in natural killer cell function, whereby degranulation may contribute to reduced NK cell cytotoxic activity.

Dr Mangalathu Rajeevan,

Centers for Disease Control and Prevention, USA, with a complex gene ME Essential Summer 2014

SECOND DAY

l autoimmune disease? include the ability to reproduce the disease by serum transfer from mother to newborn child – as is the case with the rheumatic disease, lupus. Indirect evidence would involve reproducing the disease in an animal model.

Neither form of evidence currently applies to ME/CFS. Circumstantial evidence of a link to autoimmunity in ME/CFS involves: l The presence of autoantibodies – antibodies that are made against the body’s own tissues. Low levels of some types of autoantibodies can be found in some people with ME/CFS. However, the presence of autoantibodies does not automatically mean that someone has an autoimmune disease as they can also occur in normal healthy people. l Associations with other auto-

immune diseases (which can occasionally occur in ME/CFS) and the presence of HLA antigens. l A strong female sex bias and a beneficial response to treatment with immunosuppressive drugs – both of which may apply to ME/CFS. There are other features of ME/CFS – including the often quite significant beneficial effect of pregnancy – that occur in autoimmune diseases.

Although Professor Rose’s presentation concentrated on the wider picture of autoimmunity and disease, the content was highly relevant to the current discussion as to whether there is more to ME/CFS than just an autoimmune component. Could we actually be dealing with an autoimmune disease? The jury is still out on this one...

nd infection took centre stage expression study that identified differential methylation of genes in several pathways in ME/CFS. Among the important findings from this study was that while the ME/CFS patients had decreased methylation and increased expression of TERT (telomerase reverse transcriptase) they had shorter telomere length.

CS note: Telomeres are the end parts of chromosomes and in this study they were shorter than healthy controls. Telomere length is a marker for how quickly cells are ageing – a process that has been linked to stressful life events. So a short telomere indicates that cells are ageing more rapidly – a finding that is also linked to an increased vulnerability to various age-related diseases.

Dr Mady Hornig (Director of

Translational Research, Columbia University, New York) with a poster presentation on “Immune signatures associated with cognitive dysfunction ONLINE SUPPLEMENT

in ME/CFS’. Among the results from a study involving 298 patients and 348 controls was elevated levels of interferon gamma that were strongly associated with cognitive impairment and that cognitive impairment is associated with specific patterns of elevated cytokines.

These findings, which involved comparing a highly impaired subgroup with a low-impairment subgroup, may represent a sub-group with a higher probability of viral triggers and/or persisting infection.

VIROLOGY The second session on Friday morning, chaired by Professor Jose Montoya, covered the role of infection in ME/CFS.

Dr John Chia, from EV Medical

Research in California, gave two presentations on how his group still believe that chronic enteroviral infection in the stomach plays a key role in perpetuating ME/CFS in some

cases and how chronic enteroviral infection is also related to a condition called chronic pelvic pain – where the group have found enteroviral infection in the ovarian tubes.

Professor Tony Komaroff

made some very valid comments, which I share, on the persisting enteroviral presentation in his closing summary: Dr. Chia reported again at this meeting, as he has in the past, the latest summary of data from a remarkable report and a remarkable amount of work, on enterovirus antigen and nucleic acid found in biopsy samples from stomach in cases and control subjects.

He found very marked differences in the frequency of both antigen and nucleic acid in CFS patients compared with controls.

He then also reported that when you took the biopsy specimens that these tests suggested contained enterovirus and injected them into mice, when you sacrificed the mice, there was evidence of enteroviral infection, in the mouse.

To me, these results are very impressive, but it’s also depressing to see that, to my knowledge, no academic enterovirologists have sought to try to reproduce this, not even in bulk, to take the samples that already have been collected at enormous effort by Dr. Chia and test them themselves to see if they get the same results that Dr. Chia does.

It’s a great shame and I hope it changes.

Dr Santa Rasa, from Latvia,

presented results suggesting a role for a viral infection called parvovirus B19, which can cause joint symptoms in some people with ME/CFS. Turn over 7

SECOND DAY

From last page

ALLERGY, IMMUNOLOGY & INFECTION The final session summarised some of the key results from a large and impressive multicentre Chronic Fatigue Initiative (CFI)-research that has been funded by the Hutchins Family Foundation.

that have been collected by Dr Dan Peterson.

Overall, the research group was unable to identify any specific infections in blood (serum) samples that appear to be playing a role in maintaining ME/CFS.

Dr Wang Tian-fang from Beijing

described the use of an exercise programme called Baduanjin – a set of qigong exercises that originated in China and are now practiced throughout the world – in people with chronic fatigue.

CS Note: This does not exclude the possibility that evidence for persisting infection could be found elsewhere – for example in white blood cells, or tissue samples.

Dr Takakazu Oka from Japan

The CFI involves a number of wellknown US researchers – including Lucinda Bateman, Dan Peterson and Nancy Klimas – who have looked for evidence of a wide range of infections in blood, plasma, serum, tear and urine samples in a large number of ME/CFS patients and healthy controls.

Changes in the levels of some immune system chemicals called cytokines were found in the spinal fluid samples – where there was a significant difference between people with short and long duration illness.

As a result, a vast amount of important data has been collected on demographics (age, sex, social class, education, etc), clinical presentations (which symptoms are more common or characteristic – post-exertional malaise being the most important), symptoms (and how they can change over time), associated conditions which appear to be more common (eg fibromyalgia, hypothyroidism), routine blood test results, effective and ineffective forms of treatment, outcomes (including causes of death), as well as the role of infections in ME/CFS.

TREATMENT

reported on a home-based selfmanagement programme for people with severe ME/CFS involving relaxation, pacing, coping strategies and social support. The programme was supported by a National Institutes of Health grant and resulted in improvement in the functioning and a reduction in depression – where this had occurred.

Professor Mady Hornig,

Associate Professor of Epidemiology, Columbia, closed this session with more detailed information from the pathogen and pathogenesis study.

This has been designed to identify infections that appear to be involved in triggering and possibly perpetuating ME/CFS, along with identifying biomarkers that could help with subgrouping people under the ME/CFS umbrella. This research also includes a study of cerebrospinal fluid samples 8

Friday afternoon kicked off with a session on management chaired by

Dr Dan Peterson.

Nicole Baldwin, St Olaf College,

Minnesota, described how a measure called hours of vertical activity (HVA) during the day could be used as part of the assessment of both activity and orthostatic intolerance (OI), as well as an outcome measure for clinical trials.

She presented data on people with ME/CFS who had significant problems with orthostatic intolerance and had been treated with a drug called midodrine – which acts by constricting the blood vessels and improving blood flow to key parts of the body.

Most benefit was obtained from a regime that involved regular doses every three to four hours (because the drug has a short half life) when upright.

Overall, midrodine produced a small but clinically significant increase in HVA in patients with ME/CFS and OI. 2 More information on midodrine – which is not licensed for use in the UK – can be found in the treatment section of the ME Association’s Purple Booklet, which is now in its heavily revised seventh edition.

presented the results from a small trial using Isometric Yoga in the management of ME/CFS

Professor Fred Friedberg

Friday afternoon concluded with a session on the diagnosis and management of difficult clinical cases. Several of the IACFS/ME physicians presented details of real life cases where there had been difficulties with either diagnosis or management – each case being discussed by members of the audience.

Among the interesting cases presented was one from Dr Ros Vallings in New Zealand, involving low testosterone levels and another where the use of antiviral medication might be considered.

It was interesting to note how the American doctors make far more use of vitamins (especially vitamin B12 and D), supplements (Co-enzyme Q10 is very popular) and drug treatments, especially antiviral and immunomodulatory treatments. All of these would all be regarded as highly speculative and not therefore endorsed by NICE here in the UK! ME Essential Summer 2014

THIRD DAY

The master of case definition helps stack the cards in good order – but it’s still a minefield!

Case definitions for research and practice – chaired by Professor

consensus-driven ones such as most of those that are currently in use.

They are also far better at defining sub-groups.

Director of the Centre for Community Research, DePaul University, Chicago (pictured right), gave an excellent presentation in which he traced the history of how all the various ways of defining who should have ME and CFS – eg Holmes, Fukuda, Canadian, London, Oxford – have occurred and how they all vary in the type and number of symptoms required.

To use Professor Jason’s Powerpoint slide analogy, this is all rather like a house of cards. If the case definition of an illness is weak, as is the case with ME/CFS, everything else that rests on the case definition – finding a cause, biomarkers, sub-grouping and effective forms of treatment – is more likely to fail.

Fred Friedman Professor Leonard Jason,

The use of diagnostic criteria that do not require the presence of cardinal symptoms of this illness – postexertional malaise and symptom exacerbation in particular – may not accurately identify people who have ME/CFS and could also include others who do not.

On the other hand, diagnostic criteria that require seven or eight core symptoms could increase the rates of psychiatric co-morbidity. And the current use of consensus-driven definitions may lack construct validity, again resulting in inaccurate diagnosis.

Empirically-derived case definitions, he argued, are superior to

PUBLIC HEALTH RESEARCH Saturday continued with two sessions on public health that were chaired by Dr Lily Chu, IACFS/ ME Board member, and Dr Elizabeth Unger, Chief, Chronic Viral Diseases Branch, Centers for Disease Control and Prevention, Atlanta.

Dr Nicoletta Carlo-Stella, Pavia, Italy, presented results from a study involving 89 self-referred patients which again demonstrated that a significant proportion of people with self-referred chronic fatigue (60% ONLINE SUPPLEMENT

Professor Jason concluded by reviewing some statistical approaches – factor analysis and data-mining in particular – that could help to solve how we can more accurately define people who have, and do not have, this illness.

Samantha Johnston, Griffith University, Australia, presented preliminary findings that suggest the new International Consensus Criteria (ICC) case definition identifies a subgroup of patients within the 1994 CDC (Fukuda) criteria with more severe impairment to their physical and social functioning. In addition, the ICC may be more effective at detecting salient differences in immune system function found in ME/CFS. in this sample) do not have a diagnosis of ME/CFS when they have gone through a thorough clinical assessment involving history, examination and blood tests.

Tina Tidmore and Lori Chad-Kroger (from Tidmore

Communications, USA, and the PANDORA organisation) spoke about the practical challenges facing people with ME/CFS when it comes to increasing knowledge and interest in the illness among medical students and doctors, and creating a specialist referral centre where no such facility exists.

Commenting on the issue of case definition in his closing remarks,

Professor Tony Komaroff

stated:

In terms of whether all investigators should use a common case definition, yes, that would be the ideal. I think the problem is that not all investigators agree on what’s the best and easiest to implement case definition, and part of the problem with choosing any one (definition) is that, if there is a lot of literature already that uses another case definition besides the one that you regard as currently best, it’ll be hard to compare the results of any studies going forward with the published research that already exists.

So I don’t think there’s a good answer to that question and if there is, I don’t have it.

Dr Alegre Castro-Marrero,

University of Barcelona, Spain, presented information from a family aggregation study. Of 1140 ME/CFS patients included in their DNA (= genetic material in blood) bank 13% had a family history of ME/CFS; 12% fibromyalgia; 8% immune diseases; 7% rheumatic diseases; 10% thyroid disease.

Dr Eliana Lacerda and Continued on next page 9

THIRD DAY

From last page

PUBLIC HEALTH RESEARCH Erinna Bowman gave excellent

presentations covering how the UK ME Biobank had been set up through a partnership involving both patients and researchers and what had been achieved during the first two years of operation. They also covered the work that is now being carried out following the award of a major grant from the US National Institutes of Health to study both the virology and immunology of ME/CFS. 2 The ME Biobank at the Royal Free Hospital in London is funded (c £160,000 per annum) by a joint charity initiative involving Action for ME, ME Research UK, The ME Association’s Ramsay Research Fund and a private donor.

By the end of August 2013, 104 cases and 69 controls had donated blood samples and provided accompanying information on a wide range of clinical and socio- economic variables. l More information on the work of the UK Biobank can be found here: www.lshtm.ac.uk/itd/crd/research/ cure-me/ukmecfsbiobank/

Margaret Parlor, President of National ME/FM Network, Ontario, Canada, presented data on the prevalence and health-related characteristics of ME/CFS, fibromyalgia and Multiple Chemical Sensitivity from a Canadian Community Health study. The prevalence of one of more of these conditions was estimated to have risen from 4.2% in 2005 to 4.9% in 2010.

Professor Dana March,

Columbia University School of Public Health, presented further data from the CFI study on the natural course of ME/CFS. Data comes from a multi-site epidemiological study involving 1,430 patients who had been ill for more than five years.

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In this particular group, the mean duration of illness since diagnosis was 15.4 years. One third reported an episode of remission, which had lasted for a year (median). Viral symptoms – sore throat and lymph node tenderness – showed the most improvement over time.

Dr Lucinda Bateman, University of Utah, presented further data from the multi-site epidemiological study on what treatments appear to alter the course of ME/CFS.

The most effective treatments included self-help strategies (65.2%) such as rest (37.2%), diet (20.9%) and exercise (18.9%) followed by traditional medicine (53.3%), such as prescription drugs (38.2%) and vitamins (16.4%). A small proportion reported benefit from alternative and complementary treatments, such as herbal remedies.

Salima Darakjy, Columbia

University School of Public Health, presented evidence on co-morbid and consequent conditions from the multisite epidemiological study. The most common post-diagnosis conditions reported were fibromyalgia (61%), depression (47.7%), anxiety (39.7%) and hypothyroidism (35.0%).

The presence of cancer, skin cancer in particular, in this group was substantially higher than in the US population as a whole.

CS note: The incidence of hypothyroidism in this sample is very high and has not been reported in any other study. And there is no sound research evidence linking hypothyroidism in ME/ CFS. This result is covered in more detail in a poster from Dr Lucinda Bateman where she suggested that these patients are receiving chronic thyroid supplementation without a true diagnosis of thyroid disease in an attempt to treat ME/CFS symptoms – a practice that does not have established long-term efficacy or safety.

MORE EXER

PLAIN

PROVOCATION STUDIES

CS note: These are studies that are based on the fact that if a person with ME/CFS is subjected to a stressor that makes them feel worse – exercise being a prime example – then using this, or even a double dose in the case of exercise testing, as part of a research study should help to increase our understanding of disease causation.

When you’re not preaching to the converted...

Over lunch I took part in a very constructive Special Interest Meeting chaired by Dr

Susan

Levine, Visiting Fellow, Cornell University, New York, on the subject of Medical Education.

This involved a small group of clinicians and researchers discussing how medical education to the whole spectrum of health professionals should be taken forward.

It was interesting to hear the American perspective and I described some of the initiatives that are taking place here in the UK regarding medical education.

Saturday evening brought some light relief with a Gala Dinner – giving everyone an opportunity to relax and listen to Dan Peterson’s entertaining history of ME/CFS following the outbreak at Lake Tahoe, Nevada, 30 years ago.

ME Essential Summer 2014

THIRD DAY

RCISE WORKOUTS – or just

PROVOCATION? Staci Stevens, Founder of the

heart/ or lung disease. The second involved submaximal exercise testing using near-infrared spectroscopy (NIRS).

Professor Betsy Keller, Ithica

Dr Ruud Vermeulen, CFS/ME Centre, Amsterdam, gave results from a study where oxygen extraction and lactate were lowered during a cardiopulmonary exercise test – suggesting a downregulation of carbohydrate metabolism.

Workwell Foundation, chaired the final session of the day on several provocation studies.

College, New York, presented further data on exercise testing in ME/CFS. Results showed the superiority of having two consecutive cardio-pulmonary exercise tests to evaluate functional impairment in ME/ CFS (which produced abnormal VO2max in 95% of patients) compared to a single CPET, submaximal workload of VO2 max prediction, or a standard validated VO2 prediction equation.

Professor Mark VanNess,

University of the Pacific, presented results from two exercise studies.

The first found diminished ventilation during exercise in ME/CFS patients – which was not seen in people with

Dr J Alegre, University of

Barcelona, Spain, described a study that found that people with ME/CFS have differences in adaption to physical exercise from the cardiopulmonary and hormonal view.

This involves less economical ventilation, reflecting a possible alteration in alveolar-capillary exchange, or even mitochondrial dysfunction at a cellular level.

The hypocortisolaemia (= lowered level of blood cortisol) observed after exercise stimulation may help to explain why people with ME/CFS may not cope with stress.

In summing up these studies,

Professor Tony Komaroff

wrote:

What we heard from several

groups is that, although on a

single exercise study CFS

patients did not consistently

perform below the levels of

healthy controls, of which there

are abundant normative data,

when those patients were

exercised 24 hours later again,

you saw all sorts of abnormalities

popping out.

And you did not see that not

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only in healthy control subjects

but you do not see, we were told

that degradation in performance

,

on the second test, in people with

heart disease and lung disease,

who are the main people who get

these kind of exercise study.

So it doesn’t say that this

degradation on the second day

is unique to CFS, but it says that

in their experience – long experi-

ence as exercise physiologists

– they haven’t seen it before.

And that’s probably telling us

something about this illness.

11

FINAL DAY FOURTH DAY

SUNDAY COMES AND WITH IT A MORNING DEDICATED TO CHILDREN’S RESEARCH

American conferences are hectic – so there was no time for a leisurely Sunday breakfast. We had an 8am start!

Concluding sessions covered Paediatrics (chaired by Professor Leonard Jason and Dr Rosemary Vallings) and Neurology (chaired by Professor Tony Komaroff).

ADVANCES IN PAEDIATRIC ME/CFS RESEARCH Dr Sarah Knight (Clinical neuro-

psychologist, Royal Children’s Hospital, Melbourne) presented data from a survey of Australian paediatricians. This showed a wide variation in diagnostic and management practices which probably reflects lack of knowledge about diagnostic criteria (over 50% did not use published criteria or case definitions) for ME/CFS and paucity of management guidelines.

Professor Peter Rowe

reported on new research involving adolescents and young adults with ME/CFS near the start of their illness. This group had a higher prevalence of what is termed impaired range of motion (ROM) of the limbs and spine than healthy controls matched by gender and joint hypermobility (which is an occasional co-morbidity linked to ME/CFS in this age group).

This is an important new examination finding that does not correlate with levels of inactivity. Treatment aimed at improving any restrictions in movement should help increase tolerance to activity and exercise.

Jeanna Harvey (medical

student, University of Miami) reported on a study to test a hypothesis that, combining commonly measured laboratory test results, could help to track the course of a post-infection

12

illness and identify subgroups of patients who are more likely to develop ME/CFS. Blood samples from 301 adolescents were followed up over 24 months following a diagnosis of monospotpositive infectious mononucleosis (glandular fever). They found an incidence of ME/CFS at 6, 12 and 24 months of 13%, 7% and 4% respectively.

The preliminary results suggest that there is a dynamic (= changing) response over time for haemoglobin, biochemical markers including glucose and hormones, and inflammatory markers in the blood. These results may help to identify those who are more at risk of developing long-term problems following glandular fever.

CS note: This is a study that would be well worth repeating in adults but it would be harder to do as we do not have an equivalent specific infection in adults that often produces a prolonged fatiguing illness.

Professor Peter Rowe’s

second presentation was on the prevalence, clinical features and influence on illness severity of delayed milk protein intolerance (DMPS) in adolescents and young adults with ME/CFS. The study followed 55 consecutive cases.

DMPS was suspected if subjects reported (1) at least two of the following symptoms: gastrooesophageal reflux, early satiety/ fullness, abdominal pain and (2) improvement in upper gastric symptoms on a rigid milk protein elimination diet.

Results indicate that young people

with ME/CFS have a higher than expected prevalence of DMPS. This should therefore be considered where there are gastrointestinal symptoms present. Treatment involves strict avoidance of foods including milk protein, soya, egg and wheat.

Professor Peter Rowe’s third

presentation of the morning was on the impact of adolescent ME/CFS. Results, not surprisingly, indicate that self-reported quality of life – using the health-related quality of life (HRQOL) assessment – is significantly lower for adolescents and young people with ME/CFS.

Dr Katherine Rowe (Royal

Children’s Hospital, Melbourne, Australia) gave a really helpful presentation on which factors young people find helpful (and unhelpful) in managing their illness.

The data came from a group of 788 young people aged 6-18 years with either a Holmes (1988) or Fukuda (1994) criteria diagnosis who had been seen in Dr Rowe’s clinic between 1991 and 2009. They provided feedback on management received one to 21 years after referral. At least one return was obtained from 82% (644) of the group.

Key results included: l A comprehensive management plan was appreciated because this allowed them to gain some control of their lives again. l ‘Believing them’. l Ongoing support, particularly assistance in navigating the education system, was considered to be an essential contributor to their quality of life and ability to cope.

Turn to page 14 ME Essential Summer 2014

FINAL DAY

ADVANCES IN BRAIN RESEARCH The final main session of the conference was chaired by

Professor Tony Komaroff.

Dr Yasuyoshi Watanabe (pictured) from Japan gave an interesting overview of the integrated research project that his group have been carrying out on the molecular and neural mechanisms of chronic fatigue. This has involved looking at the possible involvement of different regions of the brain in ME/CFS and the chemical transmitter systems that appear to be involved in central/brain fatigue.

Findings so far from this group include: reduced cortical blood flow, reduced glutamate (an important nerve transmitter), reduced serotonin transport, increased dopamine biosynthesis.

The Japanese group have also been investigating the use of animal models for fatigue and the development of drug treatments aimed at the underlying causes of central/brain fatigue.

This group have now published results from a new and exciting study using positron emission tomography (PET) scanning involving nine ME/CFS patients and 10 healthy controls.

This research sought evidence of activation of important immune system brain cells called microglia and astroctyes that could then be linked to what is termed neuroinflammation in various parts of the brain.

The study found changes in the parts of the brain known as the amygdala, thalamus and midbrain regions that correlated with cognitive dysfunction; changes in the cingulate cortex and thalamus that correlated with pain, and changes in the hypothalamus that correlated with depression.

The group concluded that neuroinflammation, possibly related to ongoing activation of immune system cells in the brain, is present in wideONLINE SUPPLEMENT

Exciting new evidence of neuro-inflammation from Japanese study The research group concluded that EEG PAF measurement of cognitive ‘brain fog’ (= cognitive dysfunction) may have prognostic value and help with the clinical evaluation of patients.

Dr Mark Zinn (Stanford University

Dr Yasuyoshi Watanabe spread areas of the brain and is associated with the severity of neuropsychological symptoms in ME/CFS. Reference: Nakatomi Y et al. Neuroinflammation in patients with chronic fatigue syndrome/myalgic encephalomyelitis: An 11C-®-PK11195 PET study. Journal of Nuclear Medicine, 2014, March 24 (Epub ahead of print).

CS note: I am now exploring whether this type of neuroimaging study could be replicated in the UK with funding from the ME Association’s Ramsay Research Fund. A major hurdle is that this type of PET scanning is very expensive to carry out.

Dr Marcie Zinn (Stanford

University Medical Centre) presented results from a case-controlled observational study (50 cases; 50 controls) which measured a specific type of brain wave activity known as peak alpha frequency (PAF) using a 19- channel quantitative electroencephalogram (EEG).

The findings here are consistent with reduced efficiency of brain function in the thalamo-cortical connections – in simple terms, the disruption of information transfer across the computer-like networks in the brain, along with inhibition of systems involving arousal responses.

Medical Centre) presented results from a study on cortical hypoactivation using a technique called exact lowresolution electromagnetic tomography (eLORETA).

Frontal, temporal, limbic, parietal and sub-lobar regions demonstrated significantly different current densities in ME/CFS compared to healthy controls.

The findings provide further objective evidence of central nervous system dysregulation in ME/CFS and could help to explain symptoms such as problems with balance and increased sensitivity to pain.

Susan Cockshell (School of Psychology, University of Adelaide, Australia) presented the final item on research. This involved a comprehensive investigation of cognitive dysfunction in ME/CFS through a meta-analysis of existing published research in this area. She then used this information to examine cognitive functioning in a group of people with ME/CFS, along with a range of variables, that can affect cognition.

The meta-analysis of 50 published studies involving 54 cognitive function tests showed that people with ME/CFS commonly have problems with reaction time (= the speed at which the brain responds to incoming information that is either read or heard), attention and memory, performing at normal levels of tests of motor speed, visuo-spatial Turn to page 15 13

FINAL DAY

From page 12

CHILDREN’S RESEARCH l Alternative health practitioners were widely used but considered to be of l ittle value – especially when using supplements and restrictive diets. l ‘Massage’ for muscle pain and ‘good’ dietary advice was helpful. l Psychological assistance was most sought when they were recovering and evaluating how they managed adolescent development and social tasks. Many said they lost confidence and needed reassurance and help with practicalities and social milestones – friends and relationships, dress code, appearance, interests of adolescence.

like doing or watching, was important. l Social learning – what to wear, making friends, playing sports, etc - at ages 7-10 during the final years at primary school was probably more important than academic learning.

Factors that had a negative impact on recovery included: l Delay in diagnosis. l Unhelpful teachers. l Stupid advice – especially in relation to activity management.

For example: “Exercise and you will get better”. l Pushing yourself too hard to do things. l Quack cures – many were relieved when parents stopped ‘cure shopping’. l Being told it was “all in the mind”.

l Engagement in education was the best predictor of functional outcome.

l Leaving school early and moving to a job that was physically demanding.

l Having some form of pleasurable ‘out-of-home activity’ each week, where they could have contact with friends they like and activities they

During questions, I asked about the use and threat of child protection orders. Unlike here in the UK, this does not appear to be a problem that

From page 13

quality, psychiatric status – depression, anxiety, or everyday functioning.

BRAIN RESEARCH ability, verbal fluency, cognitive reasoning and flexibility and global functioning.

A range of cognitive function tests were completed by 54 people with ME/ CFS and 54 matched controls. The ME/CFS group had large impairments in reaction time compared to controls but performed comparatively well on tests of attention, memory, motor speed, verbal ability and visuo-spatial ability.

Poorer reaction times (= speed at which the brain can accurately process incoming information) were not related to ME/CFS symptoms, fatigue, sleep 14

In conclusion, the main cognitive defect in ME/CFS appears to be a slowing in the speed at which people accurately process information. This substantial deficit in information processing and working memory cannot be simply explained by disingenuous performance or higher levels of fatigue or depression.

In addition, as has been reported on many occasions before, the selfreported problems with cognitive dysfunction are not always matched by performance on cognitive function tests – but this is not unique to ME/ CFS.

REVISED IACFS/ME PRIMER The final session of the conference involved a presentation by

children in Australia have to face.

Seiki Tajima from Japan presented a paper on sleep education at school and how this can help to prevent non-attendance.

Dr Katherine Rowe gave a

second presentation on a study that examined whether depression at presentation of the illness impacts on functional outcomes, length of illness, or perception of recovery.

Significant depression was present in 25% compared to a base rate of depression in adolescents of 20% (sample size = 388 children with ME/CFS aged 6-18 years). Those with severe depression identified ‘not being believed’ either by family or health professionals, difficulty remaining engaged with school and severity of symptoms as being the three most important factors that contributed to and perpetuated their depression.

During questions, I asked about the use of antidepressants in children with depression. Dr Rowe said that she found a low dose of an SSRI could be helpful, especially where there was a family history of depression, and may also help with POTS.

Professor Fred Friedberg,

and a lively discussion, on the new version of the IACFS/ME Primer – which has just been published after a two-year consultation period involving feedback from health professionals and patients.

Among the contents is a significant new section on the challenges of assessment and management of people with severe ME/CFS inally, I must thank everyone at the F IACFS/ME who has been involved with the organisation of this friendly, informative and well-run conference.

I look forward to attending the next conference in 2016.

Acknowledgement: Thanks to Patricia Carter for preparing a transcript of Professor Komaroff’s closing remarks.

ME Essential Summer 2014

the IACFS/ME ADVERTS /association MEA STUFF ME

Professor Koma

roff concluded the confere nce with a well-focused summary of what he felt were the main highlights of the meeting. A YouTube audio and video recordin g of his concluding remarks can be found here:

https://www.youtube.com/watc

h?v=nyyjRdbvPj0

I will finish my report with some very quotable quotes from Tony Komaroff:

ME QUESTION TIME

ME

association Liskeard Public Hall, Cornwall

Saturday, September 28 at 2pm Panellists: Dr Charles Shepherd, PATRONS

Dr Nigel Speight, Sue Luscombe,

HRHJane The Duke Kent Colby andofCarol Wilson.

KG GCMG KCVO Free entry – just turn up on the day!

Case-controlled studies comparing patients with CFS to both disease and comparison groups and healthy con trol subjects find robust evidence of an underlying disease process invo lving the brain and autonomic ner vous system; immune system; energy metabolism and oxidative and nitro sati ve stress.

Etain, Lady Hagart-Alexander

It was a fair question 30 years ago to ask whether people with these symptoms might be expressing psy chiatric distress, amplifying normal body sensations or even fabricat ing for secondary gain…but this is no longer a fair question.

BOARD OF TRUSTEES

In summary, the illness is not sim ply an expression of somatic symptoms by people with a primary psychological disorder.

Professor Peter Behan Rt Hon John Bercow PC MP Dr Anne Macintyre

Chairman: Neil Riley Vice-Chairman: Rick Osman Hon Treasurer: Ewan Dale Trustees: Martine Ainsworth-Wells, Dr Charles Shepherd, Nicki Strong Associate Trustee: David Allen Company Secretary: Gill Briody Hon Medical Adviser: Dr Charles Shepherd Hon Paediatric Adviser: Dr Nigel Speight Hon Dental Adviser: Dr Richard Cantillon

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ME Essential ISSN 1747-1737 Special online supplement to Issue No 128 © The ME Association 2014

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DES: BLOOD TESTS LU C IN TS E FL A LE T N NGE OF MANAGEME OUR EXTENSIVE RA ENT l NEW AND M E G A N A M Y G R E N E l ILITY RATING SCALE B A IS D l D E IN A PL X E H LERANCE l STOMAC TO IN C TI A ST O TH R ATMENTS l O EXPERIMENTAL TRE LLING IN THE FORM FI TO E ID U G – SA E EL SYMPTOMS l AND IRRITABLE BOW

ME Essential Issue 128 Spring 2014

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ME/CFS/PVFS An Exploration of the Key Clinical Issues

Purple booklet goes global!

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A classic account of the 1955 outbreak

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