Extraordinary NIH ME/CFS study may be most comprehensive and in-depth ever


Update (Sunday March 6, 1630 GMT): NIH drops FMD control group

I’d asked Dr Vicky Whittemore is she had any corrections to the content and got this reply:

The only correction I have at this time is that it has been decided that they will not include individuals with functional movement disorders in this study

Thank you, NIH

Dr Avindra Nath will lead the NIH's new ME/CFS study Dr Avindra Nath will lead the NIH’s new ME/CFS study

Blink and you’d missed it. In just six minutes and six slides, Dr Avindra Nath unveiled one of the most in-depth, comprehensive and innovative ME/CFS studies ever proposed: it’s the first fruit of Director Dr Francis Collins’s ‘new start’ for ME/CFS at the US National Institutes of Health (NIH). There wasn’t a lot of detail, but even from the preliminary information that’s available it’s clear that we’re looking at a very impressive project.

Since it was first announced, concerns about the study—including the selection criteria, the choice of control groups and the views of some of the researchers on the team—have dominated discussion in the ME/CFS community. During questions after his presentation, Nath said he was keen to have input from patients, citing his admiration for the role the patients’ group ACT UP played in research during the early AIDS epidemic. Carol Head, CEO of the Solve ME/CFS Initiative, has had encouraging discussions with Dr Vicky Whittemore of the NIH about patients’ concerns. She’ll discuss further with the NIH on March 8th, and I hope the NIH will engage with those criticisms then.

But looking closely at what we know so far about what the NIH is planning, it’s clear that it’s applying some extraordinary science to the problem of ME/CFS, science that could make a huge difference—despite the potential pitfalls.

The NIH is devoting some of the remarkable firepower available at its Intramural Center to probe deeply into the disease. When the study is done, researchers will probably know more about the 40 patients included than any other individuals in the history of ME/CFS, with the possible exception of the severely ill patients being studied by the End ME/CFS Project.

Some of the NIH clinical center's firepower will focus on ME/CFS The NIH will train some of its clinical research center’s firepower on ME/CFS

Dr Nath, who is Chief of the Section of Infections of the Nervous System at the NIH’s National Institute of Neurological Diseases and Stroke, will lead the study: and he believes the immune system is where the action is.

He commented that many studies find interesting — but mostly inconsistent — immune abnormalities in patients, and that ME/CFS often begins with an infection. He said the promising results from pilot treatment studies with rituximab (which targets antibody-producing B cells) also pointed to a key role in the immune system, at least for some patients.

Dr Nath said, “Our hypothesis is that post-infectious ME/CFS is triggered by a viral illness that results in immune-mediated brain dysfunction”.

The NIH is taking a very thorough approach to investigating immune (and other) problems. Although it’s relatively small, with 40 patients and 60 controls, the study is extraordinarily comprehensive, with two more studies due to build on its results, culminating, it’s planned, in trials of immunomodulatory agents.

Study highlights

  • The study will take an astonishingly in-depth look at the immune system, both via the blood and spinal fluid. On the basis of the initial findings, the NIH will decide where to target even more sophisticated tests.
  • The researchers will use a wide range of measures: thinking tests, metabolic tests that even measure how much energy patients burn as they sleep, autonomic function tests, and self-reported fatigue alongside activity measurement.
  • Best of all, the study will look at how most of these measures are changed by exercise, focusing on the core feature of ME/CFS.
  • And they will use two types of technology to probe what happens in the brain when patients are hit by exercise.
  • The most ambitious part of the study will use cutting-edge technology to try to reproduce in the laboratory the clinical or biological abnormalities seen in patients. It could dramatically speed up understanding of the illness and the development of treatments.

The hope is that this intensive approach will crack open the illness so researchers can see more clearly what’s inside – providing clues that could help reveal the mechanism of the illness, and lead to treatments.

Details of the study

Please note that most of this article is based on Dr Nath’s brief talk and slides at the CDC Grand Rounds in February 2016, and because details were quite sparse I’ve included a little information from the prematurely published (and then withdrawn) study protocol. I haven’t had the chance to fact-check my report with the NIH and so any errors are mine.

Patients and controls

The NIH will recruit 40 ME/CFS patients, who will be thoroughly assessed and diagnosed according to the Canadian Consensus Criteria (generally thought to be the most rigorous case definition for diagnosis), as well as meeting the 1994 Fukuda/CDC criteria. Patients must also have a documented infectious onset at the start of their illness, such as glandular fever — because this study is pursuing the hypothesis that an initial infectious illness triggers long-term problems in the brain. By focusing only on those with an infectious onset the NIH believe they will get a cleaner, more consistent group, making it easier to detect real, relevant differences among the inevitable random variation between patients. Patients also need to have been ill for between six months and five years and to have post-exertional malaise — the cardinal symptom of ME/CFS.

Those with a confirmed diagnosis then come back for a week as in-patients for an incredibly detailed evaluation.

Along with 20 healthy controls will be 20 post-Lyme disease patients who no longer have fatigue and 20 patients with functional movement disorder. These are patients with movement problems that are considered to be psychologically caused—one of the concerns that the ME/CFS community has about the study.

That’s a total of 100 people, making this a relatively small study and increasing the chance of false positives. However, the next phase of the study will be a validation of findings from this initial phase, which increases the likelihood of robust findings emerging.

Four aims

Nath outlined four goals of the study.

1. Detailed assessment of patients (phenotyping)

Phenotyping aims to describe patients in as much detail as possible. Beyond the assessments needed for diagnosis itself, researchers will check patients for neurological problems (including a brain scan) and will test basic autonomic body functions such as sweating and breathing, blood pressure, heart rate and tolerance of being upright. Experts in infectious diseases will assess patients. And researchers will also test memory and thinking performance, and monitor fatigue and activity levels — and test exercise capacity. Not a bad start.

2. Understanding the biology behind patients’ problems with exercise

Researchers will home in on the central feature of this illness — how exertion wreaks havoc — by looking under the hood both before and, critically, after exercise.

They will focus on the brain using functional MRI scans, which show which brain circuits are in action (the provisional protocol said patients would be doing thinking and exercise tasks during these brain scans). This should help reveal what’s happening in the brain when patients are exhausted.

For the first time in ME/CFS, researchers will also be using a remarkable technique called transcranial magnetic stimulation to probe brain function. It uses magnets placed around the head to generate tiny electrical pulses in specific places in the brain, and researchers can check if the body responds to, say, activation of the brain’s movement centre, in the way it should. The technique has been used to diagnose conditions such as multiple sclerosis and Alzheimer’s disease.

Not only will the researchers measure patients’ energy use during exercise, they will also measure how much energy patients use as they sleep and rest before and after exercise, using a sealed metabolic chamber. This is another first in ME/CFS research.

The thinking and memory tests, and body function (autonomic) tests done before exercise will be repeated after to see what changes.

An possible downside of using exercise testing – which could prove so valuable – is that it might only attract patients who don’t have a strong reaction to exercise, which might bias results. Though the fact patients are in hospital for a week eases the strain, and patients might be willing to suffer a lot from exercise if the believe the study is important.

3. Identifying immune system and microbiome abnormalities

This is where the researchers will zoom in on cellular and molecular problems.

The NIH will cover the basics by measuring cytokines, which essentially show the immune system talking to itself and to the rest of the body, and by identifying the number and type of different immune cells (such as antibody-producing B cells and natural killer cells). These have been studied quite a bit in ME/CFS, as in last year’s finding from Columbia University that cytokine levels are elevated in patients who’d been ill for under three years, compared with those who’d been ill for longer. But the NIH will be going beyond previous work by doing this for spinal fluid as well as blood in the same patients. This will give an indication of what’s happening in the brain, and in addition, they’ll look for autoantibodies that could attack the brain. The researchers will also look for any viruses that might be present, with a particularly in-depth approach for Herpes viruses.

But there’s a lot more.

Researchers will be sequencing T-cell receptors, which are a part of the immune system and are similar to antibodies in that they show which targets the immune system has already learned to identify as a threat. Each person has at least 100,000 of these receptors, and this will be one of the first ME/CFS studies to look at them. This may provide clues as to what might be driving problems in the immune system.

The researchers will also be looking at all the proteins in blood and spinal fluid: Dr Nath said they can detect at least 1,500 different proteins — proteins that will give clues about how cells are functioning, which types of cell are most active and how they are interacting with one another.

On top of that, the team will spy on what cells are doing using metabolomics. As cells do their work, they leave fingerprints behind in the form of specific chemicals, and these can provide a snapshot of how the cell is functioning at that moment. If unusual patterns are found in these chemical fingerprints, that could provide a clue about what’s making patients sick.

This in-depth approach to the immune system might sound familiar — Professor Ron Davis is using similar approaches to the immune system, including sequencing T cell receptors, as part of the Open Medicine Foundation’s Severely Ill study (as well as probing the immune system in other sophisticated ways that don’t feature in the NIH study).

Extraordinarily, Nath said the detailed immune profiling is just an initial screen to spot where the real problems are likely to be, so that the researchers can home in on them with the most appropriate tests. He said that this two-step approach was needed “because there are innumerable amounts of very time-consuming, tedious assays for each cell type that you could potentially do, or interactions between cell types”.

Note that point about interactions between different cell types. Nath said he’d consulted with NIH systems-biology and immune-cell expert Dr Ronald Germain, who specialises not just in how each type of immune cell works (or goes wrong) but also in how they interact. Perhaps the problem in ME/CFS will be in how different immune cell types interact rather than in a single cell type. And the phenomenally complex immune system is all about how the many different immune cells come together to produce a co-ordinated response.

And if all that isn’t enough, the study will look at both the gut and oral microbiomes, both before and after exercise.

4. Reproducing ME/CFS in living systems in the laboratory

Up to this point, the NIH plan is largely to pursue existing research angles, often pushing them further and bringing together many, many approaches in a single intensive study. But they are also cutting loose and trying to recreate the illness in the laboratory, using tissue from patients.

Growing neurones in the lab

A challenge in studying a disease like ME/CFS that affects the brain is that you can’t snip neurones out of the brains of living patients to find out what’s wrong with them (at least not without doing grievous harm!). The NIH is planning to use some amazing new technology to get around this problem: they’ll take blood stem-cells from patients and use adult stem-cell technology to turn those cells into neurones — neurones that are still essentially patients’ cells.

From patient blood stem cells to neurones. Image from Dr Nath's recent presentation. From patient blood stem cells to neurones.  Image from Dr Nath’s recent presentation.

Researchers will check the functioning of these neurones, including their mitochondria and the neurones’ ability to generate and respond to electrical signals. Next, researchers will see if spinal fluid or blood plasma will trigger functional problems in these neurones: maybe it’s something in these fluids that’s causing the problem in ME/CFS.

Creating ‘humanised mice’ using patient cells

NIH researchers will create ‘humanised mice’ that essentially have immune systems seeded by patients’ cells. They will then test if spinal fluid or antibodies from patients will lead to fatigue or other ME/CFS-like symptoms in the mice.

Dr Nath pointed out that if these experimental systems are able to reproduce the clinical or biological abnormalities seen in these patients, it would be a huge step towards understanding the biology of the disease. And it could help develop new treatments faster.

A promising start from the NIH

In a remarkably short period of time the NIH have planned a small but incredibly comprehensive study. It not only zeroes in on the key problem of the effect of exertion, but also looks deeply at both the immune system and the brain — two areas that many researchers believe play a major role in the illness. And the NIH will try to develop disease models in the lab that could revolutionise how researchers study ME/CFS.

Nath explained that this study is just the first phase. Phase Two will follow patients longer-term and aims to validate the findings of Phase One, particularly for biomarkers. Nath said that If they manage to identify causes of the illness or symptoms, Phase Three will be an initial treatment study of immunomodulatory drugs.

My guess is that this first phase will cost at least a million dollars (a hundred people will be in-patients for a week of extensive testing) and maybe a great deal more.

An enormous amount of thought and imagination has gone into designing this intensive study, and it seems to me that Dr Nath is taking this disease extremely seriously. The study plan isn’t perfect, but it isn’t final yet, either. And it could prove to be the beginning of a new era for ME/CFS at the NIH — one that finally delivers for patients.

 

FURTHER LINKS

Video footage of Dr. Nath’s talk at CDC Grand Rounds begins at 42:35 here, and a transcript of his presentation, along with his slides is here.


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48 comments on “Extraordinary NIH ME/CFS study may be most comprehensive and in-depth ever
  1. John says:

    I haven’t read the article yet, but there are several issues I think one could raise about the current study.

    One thing that got my attention was the NIH’s hypothesis that PI-ME/CFS is the result of neural/brain antibodies. This might be the case in some severe ME/CFS patients such as Whitney Dafoe, but aren’t Fluge/Mella hypothesizing about antibodies to the endothelium? Problems with microcirculation seem like they would explain a great many of the symptoms from ME/CFS such as-

    1. Cognitive difficulties/headache- If blood isn’t getting to the brain you’re going to be hurtin’ for certain.
    2. PEM- If blood can’t get to muscles properly then you can’t remove lactic acid, which relates to Julia Newton’s acidosis work, doesn’t it? Antibodies to the brain wouldn’t really explain reduced VO2 max either, would they?
    3. Heat/cold intolerance. Again, if your microcirculation isn’t working properly you would have a hard time regulating temperature, no? For instance when my feet get cold they absolutely will not warm up without an external heat source or a half hour to an hour wrapped up in a sleeping bag under blankets.
    4. Going back to gut issues in ME/CFS, it seems like poor microcirculation to the intestines could result in bacterial overgrowth which would mess up the microbiome, which is an increasingly hot topic of research in ME/CFS and other diseases, and since brain chemicals are produced in the gut this might affect their production as well.
    5. Sleep issues? Might reduced blood flow to the brain result in kind of a ‘brain apnea’ that causes waking during the night?

    Another thing that I wish would happen would be for a completely unbiased and as comprehensive as possible ‘fishing expedition’ with next-gen technology similar to what the OMF is doing but also for prominent and longtime researchers in the field to get together and compile a ‘greatest hits’ of putative subtype biomarkers for targeted study in a large cohort of patients.

    Also, with the NIH study there is the issue of the small sample size and potential subtypes, even though they are using acute onset cases- given that post-infectious fatigue syndromes have been reported following a range of infections, from acute Lyme (although some of this could be the result of not pulsing antibiotics during the initial tx, an emerging trend in Lyme) to SARS to Ebola to West Nile to Q fever to giardia lamblia (just to name a few), the question is are these the result of one common aetiology or does each PI-CFS have it’s own distinct pathology? Then you also have Director Collins’ comment about studying post-chemo fatigue, etc. and you’re damn right the NIH has some serious ramping up to do. That’s enough work for an entire damn division, much less one team doing one study.

    One last plea to the NIH is PLEASE DO NOT FORGET THE GRADUAL ONSET CASES! I know that PI-CFS and post-chemo fatigue would seem to be the more ‘sexy’ things to study due to their more defined onset, but a lot of legitimate CFS cases had a gradual onset and have a progressive disease course and we are sick as hell just as the sudden onset cases are. Please please please do not lose us in the shuffle, we need to be studied just as comprehensively as the PI cases are.

    1. Thanks for commenting, John

      “I haven’t read the article yet, but there are several issues I think one could raise about the current study.” I’d recommend reading it (but then I would).

      A few responses to your points:

      – they are looking at brain autoantigens, but that’s just one of many possibiities they are exploring in a remarkably thorough study, as detailed in the article – it’s not a one shot approach

      “Also, with the NIH study there is the issue of the small sample size and potential subtypes,” Yes, the study is small, and might not have the statistical power to identify subgrouips (though it might if different factors cluster together).

      “the question is are these the result of one common aetiology or does each PI-CFS have it’s own distinct pathology? “Interestingly, the Dubbo studies that looked at post-infectious fatigue after three different pathogens (didn’t include Lyme disease) found no significant differences between the patients, regardless of the initial infection.

      “One last plea to the NIH is PLEASE DO NOT FORGET THE GRADUAL ONSET CASES! I know that PI-CFS”
      Dr Nath said the focus on PI cases was expedient: the commone infectious onset was likely to give patients with much more similar immune profiles than if they’d looked at all types patients. So a good place to start, but by no means a finish. I suspect that even if this study goes very well, a huge amount more research will still be needed.

  2. Ceil says:

    This research is so exciting and comprehensive. I know the patients will be chosen from among 5 ME/CFS specialists. Do you know if the ME/CFS patients have already been chosen?

  3. The study could be amazing, though with only 40 patients more work will be needed to confirm any findings. The NIH are planning a follow-up validation study too. I’m sure the patients haven’t been chosen yet as the study hasn’t yet been finalised.

  4. 40 people is VERY preliminary, especially if they are looking for so many things. Having dealt with NIH and CDC for 20 years now, this is my reaction:

    1. If they are going to use it to see if there is ANYTHING that shows up different in these patients, and then use that to move on to better-powered studies – good.

    2. However, in the past, CDC and NIH have used these small studies to “disprove” things. Which, of course, you can’t. (Popper must have been whirling in his grave.) I hope that’s not what’s going on here.

    3. I do not understand the comparison groups – they make no sense to me, and in the context of Dr. Walitt playing an important role in all this, it makes me nervous that they do not understand what M.E. is. I do not understand why they are not using, say, MS as a comparison. Or why, if they can only afford to test 40 patients, they are doing three control groups (120 more patients?) – why, if they can only afford 160 sets of tests, it’s not 80 patients and 80 controls. Certainly there are enough of us out here to be able to find 80 patients!

    4. Did the IOM and P2P reports actually happen? I have seen no references to either. While they apologized for not consulting CFSAC before deciding what they were going to do … they still have not consulted CFSAC. Consulting them afterwards is not exactly the same thing.

    5. The value of a study is embodied in the hypothesis. What is the hypothesis here? I am already frustrated that the biomarkers that we’ve been using for decades are ignored; evidence of immune defects and chronically reactivated viruses ignored. I’ve been trying to figure out what kind of hypothesis would lead to these two particular control groups. So – what is the working hypothesis? Surely we are entitled to know THAT.

    I will not apologize for skepticism – again, I’ve dealt with this institution for a very long time, and the lack of transparency in this process, the refusal to involve patients in this process – that never bode well in the past and doesn’t bode well now. IT IS NOT TOO LATE TO CHANGE THAT. It is not too late to change the design of the study. I beg NIH to rethink this.

    Otherwise, I hope I will be pleasantly surprised. But I won’t expect it.

    1. Hi Mary

      Dr Nath began his talk by referencing the NIH-sponsored P2P report (check out the transcript above).

      Like most people, I’m surprised by the choice of controls. If the kept the same total of 100 participants they could have 50 patients and 50 healthy controls, or maybe 40:30:30 with MS sick controls.

      And you’re right that this study is underpowered, which does mean they won’t be able to rule anything out or in – that will require follow-up studies. As I mentioned in the blog, the NIH are already planning a follow-up validation study, but we don’t know how big it will be.

      And i hope you and I will be pleasantly surprised by how all this winds up.

      1. jimells says:

        “And you’re right that this study is underpowered, which does mean they won’t be able to rule anything out or in ”

        But they will be able to kick the can done the road a few more years. That is always a priority for any bureaucracy, not just NIH. The CDC brags about its mult-site study it started FOUR YEARS AGO, and we have yet to see a single published study, or even an estimate of when to expect one.

        These agencies are as good at kicking cans as they are at letting their own reports collect dust on the shelf.

    2. Els VH says:

      VERY important issues raised by Marry.
      I do hope that these issues Will be submitted to NIH/dr Nath.
      Marry, i understand Carol Head Will be speaking to Nath again?
      Will You send her your very valid concerns?
      We all deserve answers to them BEFORE this study Goes ahead.
      Thank You Marry!

  5. If the moderator can contact me I can revise the above to be more specific – I do understand what they say the hypothesis is, but I am still mystified as to why they are using the two extra study groups and not just doing ME/CFS v. healthy controls. There has to be more to this hypothesis than they are saying.

    I do not understand why they reject out-of-hand the rather large body of evidence that there are CHRONICALLY ACTIVATED viruses involved, as demonstrated by testing in a fairly large group of patients. Do they not believe the tests because they don’t believe it is possible?

    1. cort says:

      Aren’t they doing really comprehensive herpesvirus testing?

  6. What a heartening start.

    And something about the title of the doctor heading it up feels comforting to me – Chief of the Section of Infections of the Nervous System. My poor old nervous system is shooting a bit of hope through all its frazzle

  7. JR stockert says:

    I am a 56 year old male in north Dakota with cfs and fibro it started after 2 surgeries 4 years ago I do have a high ebv titters but inactive been to many many doctors now can not travel well from exhaustion I am trying the guaifenisen protocol from st amand in California thought I would mention it it is helping some with the headaches and pain still exhausted and can not work I depend on my wife to work we are in the poor house because of all the medical I hope you guys get some results soon this is a awful way to live your mind wants to have a normal body to function if I can help let me know otherwise please help all of us that are in the same situation as me I am in a small town lemmon south Dakota out in nowhere please help I know this disease is complicated when I first got it I went to mayo clinic they said cfs go home no help I hope and pray you guys find something to help JR

    1. Jody Davison says:

      Hi JR, I also was diagnosed with both CFS and FM many years ago and struggled with disability for years. I have recovered on the guaifenesin protocol and live a very productive happy life now. I see you are in North Dakota. Deb Brandt is a physician’s assistant in South Dakota and is very good with the guaifenesin protocol. You can read your story of personal recovery on our local Carolinas Fibromyalgia Recovery website. Her contact email is on there too. Best wishes to you for a successful recovery! Jody Davison

  8. Janet says:

    Great job Simon!

    Having FMD controls is SCREAMING that they want to and are going to find “something” similar and Walitt is going to RUN with that.

    What other disease study has a Guru that doesn’t believe in the disease and is then in a prominent position on the research team and gets HIS control group in? Dr. Nath is not ready for this political fight.

    The study should have 100 ME/CFS patients, 50 Healthy, 30 MS, 30 ALS, 30 Parkinson’s, 30 AIDS. Open data.

    Someone with the skills needs to write the drop dead article as to how the study should be designed and why. Without mercy it needs to be stated as to why Dr. Walitt must be removed and why Dr. Lapp must never speak about the disease again. Additionally, the Reeves criteria was a political move no matter what they are saying as to it being a “filter”.

    1. Great comment, Janet. Are they still using Reeves? Then they need to read this:
      http://slightlyalive.blogspot.com/2010/02/cdc-research-on-cfs-open-deception.html

      It also might explain the degree to which we feel skeptical (and bruised). Just an additional comment on it: I was told off the record that one of the exclusionary criteria in the Wichita two-day hospital study was failing to pass a Romberg Test – which is interesting, because that is one of the tools my own doctor used in originally diagnosing me. They said (as psychiatrist Simon Wessely does) it would indicate neurological problems (which I would think would make it inclusive, but that’s not the game they were playing).

      I beg Dr. Nath to rethink Dr. Walitt’s participation and the hypothesis. I also beg him to please rethink the comparison groups. This disease has been a serious problem in the US for 30 years, and for 30 years both NIH and CDC have obstructed the creation of a strong biomedical research community – nevertheless, it has existed.

      What has happened here is a hypothesis created by people who know next to nothing about this disease is being plonked on top of us. If I may say so, yet again.

      And make no mistake about it, fellow patients: Dr. Walitt is playing with somatoform diseases here – he just thinks there’s a biological cause for them.

      Since 1998 I have known that i had the defective 37kDa Rnase-L and a severe case of HHV-6A. Later testing showed natural killer cell dysfunction (a natural killer cell function of <3%.) In 2009 , Dr. Dan Peterson did a spinal tap and found active HHV-6A and CMV in my spinal fluid. Do you think that my serious encephalitic and neurological symptoms could have had something to do with that evidence? They immune defects and viruses go away on Ampligen and come back 7-12 months off it. I am a sample of 1, but there are more like me. Many more. We have patients improving on Vistide at Dr. Peterson's (I cannot take Vistide; my liver markers shoot up).

      Please pay attention to this evidence.

      If not – then please run that hypothesis past some non-psychiatric specialists in our field before rnning with it in the first NIH internal study on our disease since Straus discovered (to his dismay) that we have abnormally LOW levels of adrenaline (patients with major mood disorders tend to have abnormally HIGH levels of adrenaline) 20 years ago.

      Or hold a workshop with recognized ME/CFS experts.

      The national research organization for this disease, the IACFS/ME (International Association for CFS/ME) is meeting in Miami in October. Put this on a workshop there. Or ask the public members of CFSAC to help you create a workshop. Ask any of us to help you create a workshop. You need to discuss the hypothesis and control groups before committing to them.

      In the beginning of 2000, ignoring the existence of CFSAC, the late Stephen Straus of NIAID (who had recently shifted to CAM) at NIH ran a "state of the science" meeting about "CFS" with the usual suspects – psychiatrists from the UK. After pressure from Congress he relented to having ONE public member from CFSAC attend (Nancy Klimas). But Congress continued to ask for a better conference. Donna Dean had just been placed as head of CFSCC, and she ran a conference the next fall that was fantastic – full of science and discussions with researchers who had previously known nothing about the disease. Unfortunately, there was a presidential shift in 2001 and CFSCC was shut down (to emerge as CFSAC three years later). Dr. Dean left, and nothing happened again until 2011, when Dennis Mangan ran another excellent State of the Knowledge conference at NIH.

      When researchers who do not know the very long history of this disease (technically going back to 1934, but practically speaking, going back 60 years to the Royal College outbreak and creation of the terms myalgic encephalomyelitis in the UK and epidemic neuromyesthenia in the US), they make blunders. They can be perfectly well-meaning, but this topic is a mine field and requires someone who knows the history to navigate it. I am discouraged that once again NIH is going off on its own, as if we were never here at all.

      This is a very raw hypothesis. I love the scientific evidence you want to bring to bear, but I wish you were working on ME/CFS – not the physiological basis for somatic disorders.

      1. Janet says:

        Why do I get the feeling this disease is going to go through a nice big cluster outbreak or two during this study. It will have an individual or two “that matters” caught up in them and everyone is going to point the finger at Dr. Nath while Walitt will slips away and hideouts in Vegas.

  9. Ruddy Red says:

    glad to read we are not examining psychogenic causes; still i agree with various patient advocates that there are various tweaks which can be made before this is a study pwme can all be proud of. i do sympathize with those who worry that with the wrong sample group, it may be another PACE trial. i do think that NIH is ignoring the glaring problem (to us sick ones anyhow) that the patients who may feel well enough to participate in this study are not likely to be representative of our population as a whole; i am still waiting to see this addressed in any of NIH’s literature re: the trial.

    1. Janet says:

      I don’t know what they think of the severely ill and if they will even tip their hats to the Open Medicine Foundation and the Severely Ill Big Data Study. I wonder if they understand this disease progresses? I was functioning until 1998 and had done so for 20 years. 2002 it disabled me and I have just gotten sicker and sicker. There was a time I could have gone through these tests but not now.

      I sometimes think PACE trial had just enough CF patients to counteract those with true CFS. Patients with CFS I think dropped out or plodded along as best they could messing up their data.

  10. There are a few facts about this study that answer some, but not all, of the issues raised in comments above.

    One, Dr. Ian Lipkin of Columbia University’s Center for Infection and Immunity has been advising the investigators on the study design and protocol, and is part of the study’s executive committee. Dr. Lipkin’s work in ME/CFS has been groundbreaking, focused on immune abnormalities in the post-infectious subset, and the NIH study will partly attempt to validate Dr. Lipkin’s findings. Dr. Lipkin and Dr. Nath have collaborated on other immune/infectious research with neurological implications.

    On questions about the control groups, Dr. Nath answered our initial questions about why they were chosen. He stated the asymptomatic-Lyme group was chosen to compare or contrast patients who had a documented Lyme infection and recovered with post-infectious ME/CFS patients who had an infection and did not recover. The goal is to show the difference in immune biology for patients with infection that went away and those that didn’t. Just days ago, Dr. Francis Collins, Director of NIH, posted a blog about new findings showing changes in gene expression in Lyme infected patients: http://directorsblog.nih.gov/2016/02/23/lyme-disease-gene-signatures-may-catch-the-infection-sooner-2/

    Functional Movement Disorder patients were chosen to contrast post-infectious ME/CFS patients with a very well-studied group of patients with clear psychological illness with neurological presentation. Dr. Nath explained that there is clear brain imaging on patients with FMD which shows where the brain signals stop between intent to move and muscle control. Contrasting that with brain imaging pre- and post exercise challenge could be illuminating.

    On viral testing, Dr. Nath said in the answer to questions at the end of his CDC presentation that they would test for active infections, 1,000 cytokines, 1,500 proteins. You can view the presentation here, it is 10 minutes and a lot of information. https://www.youtube.com/watch?v=0SnJy5AOSd8&utm_content=bufferbeda4&utm_medium=social&utm_source=twitter.com&utm_campaign=buffer

    The 3-phase study has a goal of developing a mouse model for the disease and identifying the dysfunctional cells and patterns that can lead to treatments. It is a very deep start. I hope that adds to the comments about those questions.

    1. Thanks for those helpful comments, Courtney

      “On questions about the control groups, Dr. Nath answered our initial questions about why they were chosen. He stated the asymptomatic-Lyme group was chosen to compare or contrast patients who had a documented Lyme infection and recovered with post-infectious ME/CFS patients who had an infection and did not recover.”
      > That’s certainly a good point. I know some others have pointed that a better version of this would be to use patients who had glandular fever, but then recovered. Because people with glandular fever are known to go on to develop mecfs, while using Lyme diseaase instead introduces an unnecessary complication. It’s a good idea in principle, but would be better if tweaked.

      I don’t know if it’s relevant or not, but the chemobrain paper co-authored by Brian Walitt (NIH clinical lead) stated the infectious link with mecfs was questionable. The authors were clearly unaware of the robust evidence from prospective studies that patients develop mecfs after glandular fever – which might explain why this study focuses on Lyme disease.

      “Functional Movement Disorder patients were chosen to contrast post-infectious ME/CFS patients with a very well-studied group of patients with clear psychological illness with neurological presentation. Dr. Nath explained that there is clear brain imaging on patients with FMD which shows where the brain signals stop between intent to move and muscle control. Contrasting that with brain imaging pre- and post exercise challenge could be illuminating. ”
      > I’d missed that. It would explain what the transcranial magnetic stimulation is for. Though I appreciate the logic, but it seems a bit tangential. With such a small study I’d rather see the number of patients and healthy/recovered patients increased, to improve the statistical power, rather than have a FMD control group.

      As you can tell, I really like this study, but I do think it can be improved, especially on choosing the most appropriate control groups.

    2. Janet says:

      Lipkin has a hypothesis, and a good one, that some mental health issues are caused by viruses. But I believe he is using this study to help prove out his hypothesis and we will be swept in with mental health issues. (And I have a feeling the wrong group of doctors have been treating these people all along as they probably have a Neuro-immune disease and should be treated by doctors specializing in neuro-immune diseases but since there are not enough of them psychiatry will do it and a psycho physical social label will stick. THANKS TO THIS STUDY!)

      I don’t believe any patients suffering FMD are suffering from a psychiatric related condition, they just have not found the cause. Having them as a control group will help label us.

      And when this goes wrong, all journalists and advocates who just let this happen being taken in by their double speak are going to be held responsible. Lemmings.

      There is no reason to have these co-horts and not MS or Parkinson’s, etc.

      I think all of you are so desperate for research and so taken in by their double speak and the fact that you have personal phone calls and e-mails that you are willing to look past the obvious; we are being used to prove out other theories that will help label us with psychiatric issues.

      1. Deborah Waroff says:

        Janet, I recommend checking out Donald McNeil’s article in the New York Times the other day on Zika virus and brain defects. He interviewed Ian Lipkin at length and gives more insight on Lipkin (and some other sources’) views re Zika, Rubella, schizophrenia, etc. I could be wrong, but I see Lipkin’s views as more a question of the viruses causing structural, chemical, cytokine or whatever — basically physical changes — and that what people see from this are changed physical processes and physical modifications of range and type of activities within the brain. The characterizations that people make of the resulting activities — which people classify as behaviours and which doctors and publishers classify as psychiatric or psychological — are a separate and further layer of value judgments that the virologists themselves do not assign. I’m struggling for words. But my point is that all of us with genuine M.E. seem to have ended up with microglial activation and chronic low level encephalitis and encephalomyelitis and other abnormal cytokine and hormonal activity. The virologists are looking for what causes us (and how) to get to the point of exhibiting these phenomena, while the biopsychosocio(paths) are on the other side of things, mis-attributing the symptoms caused by these biomedical-biochemical phenomena to origins from the thoughts in our head; e.g. wrong thinking or “false beliefs.” Of course, unfortunately, we do have to be concerned that the contemporaneity of the biomedical/biochemical phenomena and the downstream symptoms may be exploited by biopsychosocio(paths) to sell the services they endorse for mental health “therapies.” (Full disclosure: of course I have to worry about possibly being over-sympathetic to Dr. Lipkin and others at Columbia University because they are my home town team.)

        1. Janet says:

          FMD has been dropped.

          I am at the point I want Lipkin off the study.

          Lyme group should be dropped because they will be selecting them not just for post infection, but for mental health due to the infection.

          If he wants to prove out his theories use some other group and not ME/CFS patients. Why isn’t he doing this with AIDS patients? They have a virus. He can work out his theory with them. Oh right, because he will be destroyed by their activists.

          Walitt needs to be removed.

          1. I completely disagree about your comments about Dr. Lipkin. He has done more than most immunologists to validate the role of pathogens in causing all kinds of diseases, discovering many new viruses and what they do to immune systems. He has absolutely legitimized ME/CFS as immune dysfunction, at least in the patients he studied from 6 clinical experts, and illuminated differences in early onset vs. late stage patients, and spinal fluid differences between ME/CFS and Multiple Sclerosis. We need science, and we need scientists with the record Dr. Lipkin has seeking to discover what is distinctive about our disease and what we can do to treat it.

    3. Deborah Waroff says:

      Courtney, I was reading up a bit on FMD, and apparently it is not known for sure after all that it is a psychological disease. Some authorities think it will be shown to be a new form of neurological disease when it has been studied a great deal more. It is important as always to remain humble and keep in mind that mankind has yet to understand everything on earth. Meanwhile, there are no ICD-10 diagnostic criteria, though it is hoped such will be ready in 2017 for inclusion in ICD-11. There are DSM 5 (psychiatric) criteria, though they apparently constitute a reiteration of the DSM 3 criteria for “Conversion Disorder.”
      I applaud many of the other points you and Simon have made. I am very excited about having a mouse model at last.

      1. Thanks, Deborah

        “I am very excited about having a mouse model at last.”
        Just to clarify: this is very much an ambition, they have yet to show it will actually prove useful.

  11. Rebekah says:

    We need more research — true. However, I’m disappointed this study leaves out those of us with gradual onset CFS/FM. IMO, this would be a more thorough study if we were also included.

    1. John says:

      EXACTLY! NOW WOULD BE A GREAT TIME TO ADD GRADUAL ONSET CASES AS A CONTROL TO SEE IF ANY DIFFERENCES OR SIMILARITIES EMERGE!

  12. That’s fine for Dr. Lipkin to have that particular hypothesis – could turn out to be true.

    But this study should be about ME/CFS, and no offense to his status, not his or anybody else’s pet theories about something else. With only 40 patients, and I’m still not clear on how they are going to be chosen, the odds are this is going to be a heterogeneous group. WAY too small for any statistically significant results.

    On the other hand, I think the various things that Dr. Nath wants to do are very exciting – I think it’s terrific.

    But I really don’t think it’s either good science, or (to put it mildly) good manners to piggyback OTHER diseases and OTHER theories on top of what is going to be a very preliminary and fragile study.

    If they only have so much money, I’d be very grateful if they SPENT IT ON US.

    He is not going to nail the “cytokines cause mental illnesses and brain fog” theory in such a small study. I don’t even think he’s going to get strong enough results to suggest much about us at all.

    If they want to do this, cough up more dough. But as it is, I feel like they are stealing my money – yet again – for their own hypothesis – yet again – and risking communicating to the public that we have a psychosomatic disease (in the vernacular) – yet again.

    And NEVER underestimate the ability of the biopsychosocial mafia to get ahold of the study and spin it to their benefit. I don’t think these researchers understand the risk they have decided to take FOR US. We will be bearing the costs, they won’t. Dear Heavens, what does it take to get treated with a little respect?

    We need BIOMARKERS and we need to learn about the ETIOLOGY of OUR DISEASE. What part of 850,000 undiagnosed Americans do they not understand? Out needs are urgent.

    I want a PURE study of ME/CFS patients using Dr. Nath’s ideas. I think it would be terrific.

    Did they do this to AIDS patients?

    1. Jody Davison says:

      Forty people is so little. People with a sudden onset most likely had some symptoms previously, but to them, the symptoms were minor and just their own version of “normal.” Just speaking from my personal experience with this illness, and I am sixty years old, and was diagnosed twenty years ago, I cannot remember a time in my life when I was totally symptom free. IBS was just the norm for me my entire life up until the last eight years when I changed treatments. I simply did not know what normal digestion was or could be. Over the course of my life, whenever I had energy demands put on me, both physical and psychological, it was a challenge to meet those demands, and it took time to “bounce back” to what for me felt like “normal.” Child birth took some time to recover, surgery took a long time to recover from, the flu took quite some time, and divorce took quite some time. I am talking about over many years, of course. All these events demand huge amounts of energy, physical and psychic. Yet here I am at sixty years old and am able to do more than I had previously. Why?
      Because I finally realized that I have a physical illness that can be treated very successfully without all the multiple prescriptions. I got off all the drugs. I took charge of my life and my health, I listened to my body and I got on the guaifenesin protocol. These past eight years have been the best years of my life. I have recovered. I have minor symptoms and my spine is not totally cleared because it has some tingling, but the awful burning that would prevent me from sitting in a chair is over. Pain is very minimal, energy is good and consistent. I don’t worry about crashing. I have a positive outlook. I am very grateful.

      1. People with sudden onset can usually point to the EXACT DAY they became ill. in my case, October 24, 1994. It’s creepy.

        1. Amy Ellison says:

          I can point to January 13, 2003, as my sudden onset day. And I can count on my two hands the number of times I felt unhealthy in the 40 years before my diagnosis. I would disagree that most sudden onset patients had symptoms over the course of their lives. Yes, I caught flu (almost always in winter, traveling in crowded conditions, before the days when we washed our hands before eating in our office, or on a train, etc.) The only reason those flues seemed to take awhile to recover from is because I never learned to be sick–our family was all about “healthy is as healthy does.” So back to work or school as soon as the fever broke (so I wasn’t contagious) and back to my busy 9-6 days, a bike ride home and then a couple mile run or a 1.5 hr. yoga class. Getting back to my active, healthy activities too soon often made the illness feel like it lasted longer. My “normal” was more energetic than the avg. person my age. And I will not feel recovered until I am back to that “normal,” adding 15 or so years of aging of course. I did have stresses my life, pre-illness, but they didn’t manifest themselves in anything physical. I had labyrinthitis once, and that did freak me out for a few months and caused some anxiety, because that’s how long it took for me to go to a doctor and get it properly diagnosed. During that time I went hiking and backpacking as usual, as the condition started decreasing on its own. The only ME symptom I might have had before 2003 was orthostatic hypotension. Low BP runs in the family, I had women friends who had felt faint in the days before their periods, so it didn’t feel that weird that I could get lightheaded at that time either. It didn’t stop me from doing anything, except maybe standing up too fast after donating blood. Actually it made me look like a stronger hiker. I had to keep hiking, keep moving to keep my BP up, so I wouldn’t rest trailside the way my hiking companions did. When I got to the top or end of the trail, often before my friends, I kept pacing or I sat down then to control the big drop in BP. It wasn’t that I wasn’t body-aware, but I really did pride myself in being super physically healthy. And I don’t think I’m alone in that. My biggest measure of this illness is PEM. If I can’t take a 2 mi. run or a brisk 5 mi. hike (nothing unusual for many of my 50-something year old friends) and not feel great afterwards, not feel tired in a good way, then I’m not “normal.” I have other ME symptoms but many of them are symptoms that friends of mine with other, mostly minor, health problems share. My ME symptoms are much worse of course.

          1. Amy Ellison says:

            Slow brain and me rushing off to take care of something in the house made my comments unclear. What I meant was that when I got the flu, which was rare (6 or 7 times in my life, max) it was almost always during the winter when I was exposed to more by being indoors. And by “normal” these days, I will know it when I can run a couple miles or briskly hike at least 5 or 6 miles and feel “good tired” afterwards, or simply great, as I have all my life after getting a little outdoors workout… My sudden illness came the day after I returned from a trip to Central America, at a time when there was no more accumulation of stress in my life than at many other times. I still think that, had I a less busy and active life and actually let myself rest, I might not have pushed that illness into ME/CFIDS. That first tropical illness was gone within a few months, and I’ve never had those symptoms since; somewhere around 8 months after Jan. 2003 I got a cold, also a rarity for me, and that seemed to throw me into ME/CFIDS.

  13. Holly says:

    Thank you for writing this summary and explanation. It has helped me understand this study more. I just wanted to let you know I appreciate it.

    I do find it encouraging they have dropped the functional movement disorder comparison group if that proves to be accurate.

    1. Thanks, Holly! And yes the dropping of FMD is accurate – it came from Dr Vicky Whittemore at the NIH. The NIH haven’t yet sorted out an ‘official’ way to communicate about this project yet – I know #MEAction are encouraging them to do so – but hopefully that will change soon.

  14. Russell Logan says:

    It has been rumored that the FMD group has been dropped – I say rumored, since word of this has once again first come to us via informal back channels, rather than as a public announcement.

    The Lyme control group has some semblance of relevance, according to the NIH, because it can be compared to the post-infectious me/cfs group. This is nonsense science. There is no such thing as post-infectious me/cfs, at least not as a clinically proven entity. This is an uncontrolled variable. With only 40 patients in the me/cfs group, I’m afraid this also is a catalyst for a null result. If the basis of the post-infectious group is undermined, the Lyme group also loses relevance.

  15. What fantastic news about them dropping the somatoform comparison group. That worried me more than anything else. And I also felt immensely betrayed to once again have to stare at that word in association with us! I had been dreading the inevitable headline – either

    “Patients with CFS share brain abnormality with those who are psychosomatic”
    Or
    “Reseachers at NIH fail to find physiological abnormalities to explain symptoms in patients diagnosed with CFS or with psychosomatic illness.”

    Whew! Dodged THAT bullet, for now.

    I had not realized (must have skipped over it) that they were doing samples of spinal fluid. That’s also good.

    It is not clear how they are going to test for viruses – but all in all, they have met my major concern. And I am immensely relieved.

    1. Glad to hear it, Mary. I hope the NIH isn’t yet done tweaking the study to make it better, in response to feedback from patients.

  16. Courtney, to criticize Dr. Lipkin’s involvement in this study is not an insult to his talents, his large and impressive body of work, or his willingness to work on this thankless disease.

    In a study such as this, there are several elements:

    1. A theory
    — 1a. A hypothesis based upon the theory
    2. A sample
    — 2a. A means of putting that sample together
    3. Testing chosen to show the validity of the hypothesis, and the theory
    — 3a. Decisions made about how testing relates to the hypothesis and the theory

    All of this involves making CHOICES. The CHOICES depend on what you know. Opening it to criticism and increasing what you know makes for better choices.

    The first part involves ideas – where they come from, how you use them. Both Straus and Wessely had no qualms throwing in ideas from an 1869 book on neurasthenia and hysteria in women. I would say that’s a really bad choice.

    Fortunately, we have no one making that bad a choice here!

    A hypothesis that involved comparing ME/CFS patients to patients with “somatoform disorders” could legitimately be criticized. Why was that choice made? Patients criticized it (I imagine so did specialists in ME/CFS, behind the scenes) – and thankfully, NIH listened. They then made what I consider a better choice.

    Including Lyme disease IS ALSO A CHOICE. Why make that choice? I can’t say the answer does it for me.

    When someone makes a choice, it is not just important to be able to explain why A led to B led to C in what you chose to do. You also have to explain why you didn’t use D instead – why Lyme and not MS? I know what they said, but I do not find it a convincing argument. The decision to use Lyme as a comparison group – instead of MS – is not scientific. If anything, choose patients who had EBV and never got sick again, v. patients who had EBV and never recovered. That’s a better comparison for what they say they want to do – look at people who had a VIRAL infection and recovered as opposed to patients who had a VIRAL infection and never recovered. Unless there are other elements behind the choice that have not been divulged – say, the expectation by a researcher that the Lyme patients did have viruses after all …..

    Given that 90 percent of the adult population in the US tests positive for having had EBV at some point in their lives, using healthy controls basically accomplishes my suggestion above – it includes people who had EBV and recovered from it normally. We do not need the Lyme patients.

    Why does it matter? Well – apparently there’s not a whole lot of money! Let’s keep focused in how we use it!

    Then we move to the actual study. Here we have an problem obvious to anybody who knows anything about statistics. They are using a very small sample – 40 patients. Representing one million people!! Now, they are well aware of this. But I do not understand why not devote ALL the money to studying the patients with ME/CFS – not patients with something else.

    The problem with a small sample is that there can be as much, or more, divergence within that sample as between the ME/CFS sample and the sample of healthy normals. Folding in Lyme patients just makes that problem more difficult to handle. It adds yet another layer, making the problem of divergence WITHIN the samples, as opposed to divergence BETWEEN the samples, greater. (AND IT SPENDS MORE MONEY!)

    With no objective means to differentiate these patients – with no biomarker – the risks from heterogeneity are greater. I know they want biomarkers to emerge FROM this study, but could it have hurt to at least use natural killer cell function?

    If the sample is not chosen by means of biomarkers, it becomes important to know just HOW they were chosen, and that’s not all that clear. I have heard so many different things. Reeves – no, not Reeves. Fukuda and CCC. Well, Reeves as a filter. (That would be the WORST use of Reeves.) and the specter of the Reeves questionnaires as “operationalizing Fukuda” – something Reeves claimed which was never demonstrated – rather, to the contrary, his own study claiming to prove that had, instead, disproved it; and Lenny jason’s studies also showed that it defined a patient cohort that would exclude the sickest patients and include patients who did not have Fukuda CFS but did have mood disorders.

    The patients used by CDC in their Atlanta and Georgia studies were chosen using the Reeves questionnaires. I would worry that the 40 patients in this study would have been chosen from the CDC’s group, but apparently they are coming from a number of different practices. Less heterogeneity in some ways than the Reeves cohort, but possibly more heterogeneity if different specialists have different ways of diagnosing patients. (I assume they will include that information – there will be a variable for the practice where the patient was diagnosed.)

    Given the specter of heterogeneity, given that – without a biomarker – there is NO WAY to avoid heterogeneity in this very small sample – it is just asking for trouble to compare it with ANY OTHER GROUP yet – no matter how sensible the idea.

    All they can do with 40 patients from different practices and no biomarkers is see what turns up when they examine them for all sorts of abnormalities. And isn’t that enough? This is a PRELIMINARY study. This is not the time to make unnecessary choices. Choosing a comparison group is not a choice you HAVE to make. so don’t make it.

    So you see – this is in no way a criticism of Dr. Lipkin. It is, rather, an examination of the CHOICES being made, and questioning whether this apparently expensive study could be beefed up statistically a bit. To repeat: the best time to criticize the design of a study is BEFORE the study takes place, not after they’ve gone and spent a lot of money!

    80 patients with ME/CFS rather than 40 would strengthen the study enormously.

    So – what do we have?

    ON THEORY AND HYPOTHESIS:

    1. A hypothesis that the patients diagnosed with ME/CFS have characteristics in common that are not shared with healthy normals.

    2. A secondary hypothesis that the characteristics are, or are not, shared by post-Lyme patients.

    3. Fortunately we no longer have another secondary hypothesis that the characteristics are (or are not) shared by patients diagnosed with physical somatoform disorders. That strengthens the primary hypothesis considerably.

    4. Finally, a silent hypothesis that seems implicit in the way NIH is looking at this disease: it is all about “fatigue.” Perhaps the study itself will teach NIH what we patients have never been able to – it is NOT all about “fatigue.”

    ON THE SAMPLE:

    5. A data set that is potentially problematic because this is a very complicated disease, and there is a potential that 40 patients will have major differences.
    a. It is a GOOD thing that they are sticking to both sudden and viral onset. That is not representative of the entire body of patients, but with only 40 in the study, it WILL make the sample more homogeneous. So it is a good choice.
    b. It is unfortunate that there is no objective marker being used, because they want to test all the potential biomarkers (I guess). With only 40 patients, I think I would have picked one, say, natural killer cell function (which the IMO seemed to think was pretty close to a solid biomarker), or the 2-day CPET test. Personally, I’d advocate the 37kDa Rnase-L defect but I know I’d lose that battle!!
    c. Given that there is no objective biomarker, it is critical that the definition used be as accurate as possible. I would turn to the work of Lenny Jason for this, because I think Dr. Jason has done the best job of anybody in studying the different definitions. I would be comfortable with the CCC (2003) or the ICC (2011). I would be comfortable with Dr. Bell’s questionnaires. I would be comfortable with the questionnaires Dr. Jason has painstakingly put together.
    I am, for reasons too numerous to mention, not at all comfortable with the Reeves questionnaires (aka the Reeves definition or Reeves’ “operationalization” of the Fukuda definition – a claim that is simply not true). That would mean I am uncomfortable with including anyone from the CDC’s studies that used Reeves’ questionnaires to select patients.
    Given that the 40 patients are coming from different practices, I would emphasize again that there needs to be a variable indicating which practice they came from to perhaps explain variance within the group better. (If not statistically, then eyeballing the results!)

    ON THE STUDY ITSELF:

    6. I have absolutely no criticisms at all of what Dr. Nath has in store – to the contrary, I’m rather excited at the possibilities. I cannot disagree with these choices. I am also pleased that they are using spinal fluid samples and gut samples, because we know that our viruses, after a while, can disappear from the blood supply while remaining active in different parts of the body. (And I admit that I did not understand this when I first critiqued the study.)

    Do you now see? They have had to make a lot of choices. There is nothing wrong with criticizing these choices – with offering alternate choices, with helping them see elements of the choices that may not have been part of their experience with the disease – but is part of ours.

    This is going to be an expensive study. The time to critique the choices being made to characterize the study is now, before they spend the money. (Otherwise … well, ask the British how well that went with PACE …)

    Mary Schweitzer

    1. Amy Ellison says:

      Mary, you make great points. I’m sorry I’m not up to digesting everything now, and making similar coherent sense! I may be simplifying things (because that’s all my brain can handle at this particular moment) but isn’t the study going to use the 2-day test to make sure that the 40 CFIDS patients indeed show “PEM”? PEM has always explained, to me anyway, the difference between “BEING fatigued” and “GETTING fatigued,” which is what makes ME different from other “fatiguing” conditions. I would think that the CCC definition would require testing for PEM in the 40 samples, and I would hope that the participating medical practices would be able to properly administer the CPET test.
      I also think that they should look at 80 ME/CFIDS patients and save comparisons with Lyme, even MS, for another time…

      1. That was a good comment (your brain doesn’t LOOK sick, hahaha). I’m finding this a bit confusing – I understood them to say they were going to use CPET testing as part of the study – not as a requirement FOR the study, if you get the difference.

        I would be much more comfortable if that were a requirement for participation, although – as some have commented – it might limit the number of patients who could participate.

        If I had access to them, I guess I would suggest that the two-day CPET test be used, but if on the first day the CPET score is very low, they skip the second day. When off Ampligen, my CPET results are so bad I would be eligible on that basis alone for permanent disability (as a cardiac patient).

        1. PS – when I first went on Ampligen, I couldn’t walk, so treadmill testing (required for Ampligen) was a moot point. I remember my husband and the doctor joking about tying my hands to the treadmill rails …

          1. Amy Ellison says:

            Oh Mary, you should have seen my brain *before* my ME, how healthy it looked, ha ha ha. Ah, the brilliant comments I could have written then! Less foggy than rushed today perhaps…Not having had a CPET test I have little idea how exhausting they are. And I must say I’m concerned for the health of the people going into the study, as the study sounds grueling, especially if tests, samples, etc. are being done in quick succession. I think for most of my illness, moderate (low-moderate during relapse/crash), I would have been able to do the tests though, so hopefully there are others who can and are not currently in a big crash. Not as familiar with the CPET as I’d like to be, but are there other conditions that would produce a such bad results on the first day that a potential study participant could be mistaken for a CFIDS patient? I thought the point of the test was to confirm an aspect of PEM, to see what happened the next day, how much worse performance was and how poorly a person recovered between tests. Would it be possible for someone so severely depressed and fatigued from depression, for example, to score quite low on the first test, so if they allowed people in the study on the basis of the first day only, they’d get the wrong folks? They wouldn’t get someone with somewhat measurable PEM? Or, the CCC and ICC are good enough to screen out such potential participants, and someone like you, for example, would so clearly have CFIDS from those criteria that the 2-day test wouldn’t be necessary (to get in the study, though then you’d need to do it during the study somehow…) I admit I haven’t re-read any of the study info this past week so much of what I learned last week is gone. When I have other mental tasks to be done in life, I let myself not file too much info in my brain, which is what’s going on now. What I am clear on though, is that if indeed the FMD folks are not going to be part of the study, then like you I am breathing a small sigh of relief. I really appreciate your depth of understanding and comments here, thank you. And Simon too.

  17. The NIH study is requiring PEM as an enrollment criteria, in addition to post-infectious onset. Patients will meet CCC, PEM, IOM definitions, and post-infectious. It will not be a heterogeneous patient sample. Please see my post on MEAction outlining answers given us by Dr. Nath when details of the study first emerged: http://www.meaction.net/2016/02/09/positive-answers-to-initial-questions-re-nih-clinical-center-protocol/

    1. Amy Ellison says:

      Thank you, Courtney, for all your clear explanations and thoughts. I read something one day and it makes complete sense; then I need to study it all over again the next week cause it doesn’t automatically register in my mind. I do have the same understanding that PEM will be required for enrollment in the CFIDS sample group. I’m curious as to how they will confirm that it’s PEM, and not just “fatigue,” but I also trust that between the CCC and IOM definitions, a proper group of (post-infectious) patients will be selected. Homogeneity at this point makes sense too.

  18. Chris says:

    I’m glad that the study is focusing on people with diagnosed infections as a starting point and on the central nervous system.

    I have suffered from Epstein Barr infection with central nervous system involvement for over two decades. The virus is long gone. But the damage to my central nervous is still there (the chronic fatigue component). The fatigue is not ‘physical’ per se. I am not in any pain! Exercise (light) actually HELPS MY BRAIN FUNCTION. My central nervous system responds positively to exercise, not negatively. I can’t see how exercise would make CFS worse when all the studies show that it improves brain function in all areas. I wish I could be a part of the study.

    1. Amy Ellison says:

      Chris- I think it’s really important to differentiate between what I call “exercise” and exertion-level exercise. For me [true] exercise will always be cardio, aerobic, whatever you want to call movement that gets the heart rate up, that taxes our anaerobic threshhold, etc. That type of exercise will exacerbate symptoms in almost anyone, and the study need to focus on that. That is what PEM is, when exertion (in my case the *real* exercise) causes it. “Exercise” is something else in my book, more a type of movement that I am fortunate to be able to do most days.

      I’m not sure what type of “exercise” you are able to do that improves your symptoms, but if you mean *light” exercise (in my book that “exercise” is stretching, yoga, riding my bike very slowly on a flat area for 10-15 mins, walking easily, light weights with very few reps, etc.) then yes, though things can help some. Like you I had an infection that is long gone and I am also in little pain (and feel very blessed by that!) My neuro symptoms are still awful and no amount of “exercise” (in my case: yoga, riding bike w/o getting heart rate up, very light weights for 5-10 mins a few days a week on a good week) will improve those.

      Many people are in too much pain and brain fog for anything like the things I usually do. I do agree that “exercise” (the easy, light stuff I’ve mentioned) can help me a lot. It might keep some pain away the way I exercise (I studied dance, yoga, a fairly knowledgeable about exercise, have excellent body-awareness…) and it certainly helps my mood! Sometimes on bad days I simply lie on the bed and circle my feet, turn my body in gentle twists, contract/release my core. Of course it would be wonderful if all ME sufferers could to that (and anyone who can do that *safely,* please do…) However, I cannot do any of my exercise in bright light, heat, busy/noisy places. I can only ride on quiet cool (it’s always cool here!) evenings. I cannot go to a yoga class or gym even though I can only do most of those light activities at home. I can’t carry on a conversation, focus on anything else but the simple movements I’m doing, so I do these things alone. (Being able to do things with other people and enjoy them is another feature of *true* exercise by my definition.)

      Despite being lucky, like you, to be able to move with little pain, I have overdone it a couple times, which has caused some intense deep neuro issues in just my quads for a few weeks. If I were able to safely run again, to hike–I mean *really* hike–that would be the difference in my mind between [true] exercise and “exercise.” If you are able to truly exercise, like run a couple miles, hike a brisk 4 or 5 mi., get your heart pounding, work up a sweat, i.e. the fun stuff I used to do before ME, and feel great afterwards (like I used to), that might be a gauge that you are recovered. (“Recovery” for me is not just sitting on the porch in no pain, but doing the things that healthy active folks my age do; yes, I’m early 50s, but most of my friends are still running, training for triathlons, open-water swimming, high altitude backpacking, skiing, rock-climbing, practicing long yoga sessions several days a week.)

      If you can do true exercise and it helps you, and you don’t get PEM from it, then perhaps you have some serious neuro damage that isn’t fullblown like ME? Not sure what symptoms exercise improves for you and more importantly, what type of exercise (or “exercise”) that is. No matter how much “exercise” cheers me up and perhaps keeps some pain away, helps relax my mind and decrease a certain type of mental stress, it doesn’t make my light/noise sensitivity any better. It doesn’t make me less twitchy at the end of the day. It doesn’t make my muscles respond as strongly as they should when my brain tells them what to do. It doesn’t really make me think more clearly; if I’m having a fuzzy day that means I need to take it easy, no matter what. “Exercise” doesn’t make my ears stop ringing, nor does it help my vertigo (sitting on a bike and focusing in front of me is something that I can do, and my balance is okay then, as long as I keep coasting.) As I said, maybe all this “exercise” I can do is keeping me feeling better than I would without it, but I’d by no means say that real exercise (going for a run, for example) would improve any of my symptoms. I might be able to push myself to eek out a run, unpleasantly, but I would get absolutely no cardio benefit from it, I’d be sick for weeks afterwards; it wouldn’t make me feel great like real exercise used to do.

      I did the simple one-day cycling test for a research study. I got pretty tired, got my heart rate up–and I believe that is what a study test will look at, how a person recovers from that kind of exertion. Despite feeling like a very “fit” person with ME, I still did horribly on the cognitive/memory tests afterwards, surprisingly so. The two-day test might look at Vo2 max(?), how the body is metabolizing energy and how well the cardio-vascular system, amongst other things, recovers. (I’m sorry, I’m not too clear today on exercise physiology and the proper terms.)

      I am often tempted to send myself over the the UK to show those folks how much “exercise” treats ME, ha ha. It does not treat my ME at all!! “Exercise” is something I do as a treat to myself, as a celebration that I’m having a good day. If I’m feeling like crap neurologically (which of course translates to physical “fatigue” in the sense that my BP is too low, pulse too high and I get air hunger) then I’m not going to try and “exercise” much. I know that “exercise” isn’t going to make me any better. I might lie on the floor and do restorative yoga but that’s about it. Maybe on the bed I’ll contract my core a few times (to keep back pain at bay.) That’s hardly a “treatment” to improve the serious, disabling disease that ME is for us.

      Anyway, I digress. I’m not what studies you are referring to that says exercise helps brain function in people with true ME with PEM. The studies would have to show real exercise, at *exertion level,* and then show positive results on the battery of cognitive/memory tests. As much as I’d like to think that that type of movement would help, I’m convinced it does not, and that it does make people worse, especially those with pain who have trouble moving in the first place.

  19. Laurie says:

    Here is a 2 hour NIH video with Brian Walitt. I’m not well enough to write about it; others will have to do that.

    Demystifying Medicine 2013 – Pain: How It Happens and What Can Be Done? https://www.youtube.com/watch?v=1DTwkooHUF8

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