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Surprise of the IACFS/ME Conference: the Light Study

Discussion in 'Latest ME/CFS Research' started by Cort, Sep 13, 2009.

  1. Cort

    Cort Phoenix Rising Founder

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    This is from the Conference Overview I just put out. I found it tremendously exciting

    For the full review plus pictures

    Adrenergic and Sensory Receptor Expression on Leukocytes Increases After Moderate Exercise in Chronic Fatigue And Fibromyalgia. Allan Light, A. White, L. Bateman and Kathleen Light.


    I was fighting off sleep at this point. We’d just heard about yet another cortisol study – a subject that is increasingly wearing me out. Every conference, though, has its surprises. Dr. Bateman said the Utah Group was doing some great stuff but my mouth gaped when I heard this presentation.


    Pain Researcher: Dr. Allan Light has spent his career researching pain. Now that he’s moving into the fatigue field his assessment is that it’s about 30 years behind the pain field in understanding how the problem occurs. He believes both fatigue and pain - two symptoms produced by the brain to signal problems in the body - are created by the same type of system - an interesting theory given how many FM patients experience fatigue and how many ME/CFS patients experience pain.

    Dr. Light has done a good deal of background work to get where he could assess what might be causing the fatigue in ME/CFS. First he used laboratory animals to uncover two sets of sensory neurons that appear to relay fatigue and pain signals from the muscles to the brain. He then identified which receptors perceive signs of muscle injury. Once these receptors come across a substance which suggests muscle injury they presumably trigger those neurons to send a signal to the brain. The brain then sends out pain and fatigue messages in an effort to stop us from using those muscles.

    Researcher have never looked closely at what actually fatigue - but they are starting to.

    Dr. Light first highlighted what kind of fatigue is present in ME/CFS. Dr. Behan and Chaudhuri about eight years ago asserted that ME/CFS patients exhibit ‘central fatigue’ rather than muscular fatigue; i.e. their fatigue is not due to problems in the muscles but to problems in the central nervous system. Dr. Light also asserted that muscular fatigue - which refers to the ability to contract muscles to produce energy – is not the problem in this disease.

    But instead of the central nervous system, Dr. Light believes the problem occurs in the body - specifically in the sensors that monitor muscle health. These sensors – which are found on white blood cells in the blood - continually monitor the blood for signs of muscle damage – i.e. for increased levels of lactate, for low pH (acid)and for purines that are produced during ATP production. They include the:

    • ASICS - Acid sensing ion channel - associated with muscle and joint inflammation
    • Purinergic X Receptors (P2X4/P2X5) - sensing ATP levels - interestingly the ratio between the two may determine whether one has ME/CFS or fibromyalgia; P2X5 appears to trigger fatigue signals while P2X4 triggers pain signals.
    • Vannilloid = sensing heat, acid

    Dr. Light also examined sympathetic nervous system and immune receptors. The SNS regulates blood flows in response to metabolites produced by the muscles.

    RESULTS

    The Lights tested receptor activity at baseline when the patients were at rest and then at varying times after a moderate exercise activity. At baseline, receptor activity was similar except for a few receptors suggesting that chronic fatigue syndrome (ME/CFS) patients had increased ‘vascular resistance’. This appears to suggest that their blood vessels were narrowed - (perhaps in an attempt to maintain blood pressure in the face of low blood volume?).

    The post-exercise receptor activity was dramatically different with the visuals in Dr. Light'scharts drawing ‘oohs’ from the audience. (The healthy controls are on the bottom and the CFS/FM patients on the bottom). The receptors hardly budge in the controls after exercise but they look like Mt. Vesuvius in the CFS/FM patients. ME/CFS patients often feel like they’ve run a marathon after mild exercise; these results suggested that at least one part of their body reacted as if they had.(Remember this was after 'mild exercise'.)

    Intense exercise usually causes receptor activity to increase several hours later in healthy people but even mild exercise caused the receptor activity to increase in just 30 minutes in the ME/CFS patients; the finding surprised Dr. Light; not only did the receptors appear to be overreacting in ME/CFS patients they also appeared to be responding surprisingly quickly.

    Beginning at 30 minutes after exercise and continuing at eight, 24 and 48 hours after exercise, CFS patients showed increases of the P type of ion channel receptor activity up to four times its pre-exercise level while healthy subjects showed no increase at all. These receptors seemed especially sensitive to fatigue. The graph of the results is incredible; with CFS patients, receptor activity skyrockets while the healthy controls' results stay essentially at zero.

    The activity of a receptor called Type A that’s been implicated in pain doubled in ME/CFS patients who also had FM and showed no increase in healthy subjects at all. Sympathetic nervous system (adrenergic) receptors that detect SNS activity were increased 2-6 times.

    How active are these receptors?
    These sensors, not surprisingly, get really active in marathon runners but they still never got as active in marathoners (after a 26-mile run ) as they did in ME/CFS/FM patients (after a mild 15-minute exercise period).! (In this graph the healthy controls are on top, ME/CFS patients on bottom)

    Not Cytokines - Interestingly, given all the interest in pro-inflammatory cytokine levels, neither of the two cytokines tested (IL-6, IL-10) exhibited increased activity in the ME/CFS patients. The activity of the anti-inflammatory cytokine IL-10, which appears to be showing up again and again in ME/CFS studies, was increased.

    Muscle Damage or Sensor Problems? These sensors should react this way only if they were getting constantly triggered by high levels of lactate or acid or purines in the blood. Dr. Light didn’t check to see if those substances were present in high amounts but other studies suggest that they are not elevated in ME/CFS. The only other explanation appears to be that the receptors themselves seem to exist in a state of hypersensitivity - that the smallest amount of lactate, for instance, sends them into a tizzy and they stay that way for a long time. Even at low levels of activity, muscles will produce some lactic acid and ATP; Dr. Light conjectured that chronic fatigue syndrome patients have many times the normal level of these receptors on their white blood cells. Remarkably these receptors were still highly overactive 48 hours after this mild bout of exercise.

    FM and ME/CFS: Dr. Light’s study makes a lot of sense in several ways. It’s been difficult to find evidence of overt muscular damage in either ME/CFS or FM, yet the fatigue and pain found in those diseases is enormous. Dr. Light asserts that both diseases display deranged sensory systems; one is producing a lot of pain (and fatigue) and one is producing a lot of fatigue (and pain).

    The Source of the Central Sensitivity Syndromes?
    Both often co-occur with other possible ‘sensory’ disorders such as chemical sensitivity and irritable bowel syndrome (IBS). Given the pain evoked by IBS, researchers, for example, expected to find evidence of highly inflamed tissues; but when they examined their intestines they found no evidence of damage at all – the problem lies elsewhere - perhaps in heightened levels of pain receptors. Indeed in his paper Dr. Light reported that increased activity levels of some of the same receptors were also found in IBS patients.

    He also - in his paper - proposed a model of receptor activation to account for the orthostatic intolerance often seen in this disease. Finally he noted that the central sensitivity syndrome paradigm proposed to explain ME/CFS, FM, IBS and other diseases fits very well with this model of continuous central nervous system activation by the sensory receptors in the body.

    Unfortunately Dr. Light was severely limited by time at the conference (and came right out and said so). It seems he was given less time than he had expected –so he ripped apart his rather complex presentation and gave us the highlights. (Luckily we had some backup: Dr. Light’s OFFER Presentation and ithe publication of his paper)

    Treatment

    Is there a way out of the exercise/sensory receptor up-regulation dilemma? Not at the present time but at the 2008 OFFER conference Dr. Kathleen Light cited evidence showing that regular amounts of tolerated exercise/activity do appear to turn down the fatigue/pain response to some extent.

    Of course they are limited by the fact that "exercise even at a moderate level causes worsening pain and fatigue symptoms in these patients at 24 and 48 hours later and sometimes much longer"

    A Drug
    - Researchers have found that injections of Propanolol beta blocker in rats has helped in reducing muscle pain. The same thing was shown in TMJ patients in a single lab test. Dr. Light noted that they’d had a hard time getting this data published

    New Work: Starting with laboratory animals and moving up to healthy humans and now to fibromyalgia and chronic fatigue syndrome patients, Dr. Light is building a strong foundation for a new model for this disease. This body of work, though, is new not just to the chronic fatigue syndrome research field but to the research field as a whole. Acceptance of his ideas, if they are proved to be correct, will undoubtedly take time. Kudos therefore to the CFIDS Association of America and the National Institutes of Health (NIH) for funding such an innovative and ‘out-of-the-box’ research effort.

  2. Victoria

    Victoria Senior Member

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    Great article, Cort,

    I feel (even today - 5 days after my stress echocardiagram) like I've run a 20km marathon with a loaded gun behind me.

    I now have to walk to work in slow motion, instead of briskly, which I always did in the past (I have walked home slowly for a long time, but that was just as much about sore feet or hip as anything else).

    The pressure on my chest is still quite noticable. I am so, so tired (very different to what I have felt in the last couple of years since I have improved significantly.

    Every time I move quickly, I get dizzy.

    They spent nearly an hour & a quarter doing the test & did some parts over & over again. The scanning technician & cardiologist seemed to do many pictures about 40 times. I can't tell you how painful, pressing on my side that was (as they scan the heart between the ribcage more than the number of times on my chest).

    For the first time in a long while, that heart stress test really took the "stuffing out of me". About 5 minutes before the end I had to beg them to stop as my L shoulder hurt so much, I had to turn over & rest.

    For someone who has been so much improved for 2 years, that simple, (but painful & very stressful) heart test has put me back immensely.

    Victoria

    Ps but I sent you that article this morning never the less.
  3. Cort

    Cort Phoenix Rising Founder

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    Who knows but could Dr. light have found the key to all of these oversensitivity issues? They have to start somewhere - something has to be upregulated somewhere. We know that the pain producing pathways in fibromyalgia are highly upregulated and that the activity of the pain inhibiting pathways has been turned down.

    Now Dr. light finds that sensors responsible for fatigue in the body not the brain are highly upregulated. So are sensors that provide information on sympathetic nervous system activity.

    Does Victoria's pain during her procedure result from white blood cells frantically sending messages to the nervous system that she's being hurt and the brain responding by upping its pain signals? Lots of questions. Interesting stuff!

    But where does the upregulation start? Does it start in sensors on immune cells? And if so why are white blood cells producing so many more pain and fatigue sensing sensors than normal?
  4. Chris

    Chris Senior Member

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    Sounds good, but....

    Cort, many thanks for finding this--very interesting! But if I read it right, this suggests that there is nothing seriously wrong with those mitochondria after all--and my impression, alas, is that there really is something wrong.

    f he is right, there is maybe more hope in such approaches as the Gupta amygdala theory--but most of those who have blogged on that---including you!--seem to find that it helps, but PEM continues...? But fascinating stuff, however it ends up. Best, Chris
  5. Koan

    Koan Be the change.

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    Very interesting

    "Even at low levels of activity, muscles will produce some lactic acid and ATP; Dr. Light conjectured that chronic fatigue syndrome patients have many times the normal level of these receptors on their white blood cells. Remarkably these receptors were still highly overactive 48 hours after this mild bout of exercise."

    I've posted a couple of times about lactic acid recently. I find its connection to both Panic Disorder and muscle fatigue interesting.

    The findings of Dr. Light may explain why so many people experience some improvement in all symptoms, not just anxiety, when treated with Alprazolam (Xanax) which probably competes for these receptor sites given it is specifically a panic "blocker" and not simply a tranquilizer.

    I think what sometimes gets lost in discussions about central fatigue is that it produces an effect that is not simply one's appreciation of fatigue but an actual failure of a healthy muscle to move.

    When I began to relapse after several years of pretty good functioning, one of the first things I noticed was that I could not clap along with healthy people. My ability to keep moving my arms would fail. I did not think "Gee, my arms are tired, better stop clapping.", my arms failed. When I walk more than I am able, my legs fail. They will not move.

    The brain does not create an idea of fatigue in the mind of the patient but a situation of fatigue leading to failure of healthy muscles.

    Thanks for this, Cort.
  6. hvs

    hvs Senior Member

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    There's every chance I'm misreading the Light stuff, but I'm pretty sure that a number of people have shown that CFS patients (of the Incline variety, at least) enter anaerobic metabolism ridiculously quickly on a treadmill test. I'm not sure why special "fatigue receptors" are necessary to explain post-marathon-like fatigue, lactic acid galore, and post-exertional "malaise" (lame name, by the way). Am I missing something here?
  7. Cort

    Cort Phoenix Rising Founder

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    Its kind of an odd situation. The lactic acid stuff hasn't held up. One study found it and I think 2 later ones did not. I asked Staci Stevens of the Pacific Fatigue Lab about it; they looked in the repeat exercise tests and they did not generally find it - a rather strange situation. They've also had trouble finding autonomic nervous system dysfunction; something they felt sure was going to show up.

    So - it seems like there's metabolic dysfunction in about half the people they've tested - but caused by what is unclear.
  8. Victoria

    Victoria Senior Member

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    Koan,
    this greatly interests me too. I mentioned in another post that I had arrived home form work one night (several yrs ago) & sat down in my coat & was unable to move. Couldn't lift my arm. Like you say it's not about being tired & deciding not to move/clap, it's about being unable to move.

    I told the cardiologist today (after bad results on last week's stress echcardiagram) that I found this "fatigue" in the last couple of weeks rather weird. I am not THAT unfit. My body just won't move. I also mentioned the severe shoulder pain in the test (not chest/heart pain?).

    I wondered whether I am experiencing some sort of FM relapse (after a couple of relatively good years).

    I also mentioned to him that I wondered if all this pain/arrythmia/tachycardia was Fibromyalgia. I might add that I had a complete typed summary of the last ten years on my health problems for him (including 2 x stress echocardiagrams in 2000 & 2002) which resulted in the cardiologist at that time saying I had excellent heart health).

    It was comforting to hear this obviously, very learned & experienced Cardiologist agree that my past heart/chest issues did seem to suggest FM related.

    But this time, the stress echo cardiagram last Wednesday did show left mitral valve blockage, some malfunction in the heart muscle & small stenosis in the L aortic valve (which is what accounts for my heart murmur).

    And he agreed with last week's prognosis that I must have a coronary angiogram to rule out vessel blockages surrounding the heart.

    What a change it was to find an "older" specialist open to the idea of these FM symptoms. He was also happy to respond to my request to give me extra anaesthetic/sedation in light of my claims that 2 local anaesthetics in past years had been completely non-effectual.

    Must stop now - a bad session of tachycardia/very high BP at 2.00am this morning has left me a little shakey & unstable.

    Victoria
  9. Noah_Scape

    Noah_Scape

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    The Dr. Light theory makes things a bit clearer - it fits with the idea of "sensory processing PAIN disorder", and now includes the FATIGUE as well.

    I hope that this theory will provide some kind of easy way to explain this disordered protective system to normal people, or even my doctor. It just makes so much sense, and explains why Fibros cannot just "work through the pain" - the protective systems just get more protective and the cramps, pains, and fatigue just get worse. But I am preaching to the choir here....

    Anyhow, thanks for attending the conferance and writing about Dr. Light's theory.
  10. Frank

    Frank Senior Member

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  11. kolowesi

    kolowesi Senior Member

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    Victoria heart tests

    I just want to wish you luck on the angiogram:eek:

    So sorry you turned up with these problems.

    I'm glad you found a doctor who will listen to you about the broad scope of your symptoms, and who will try to keep you from having unnecessary pain!

    Any chance of a biopsy while he's in there? Then you could have the tissue checked for viruses and bacteria.

    On the HHV-6 Foundation website are some cardiomyopathy studies. Plus the executive director there has talked with some German doctors who routinely do heart biopsies. If I remember, they found Parvo B19 in a lot of PWME hearts; HHV-6 in a fair number, EBV in some, and hardly ever CMV. I think they found enterovirus as well, and that cleared up completely with interferon treatment.

    Don't know if you are interested in pursuing the infection angle of FM. My neurologist found mycoplasma in more than half his FM patients (active infection by PCR) and Dr. Garth Nicolson found it in around 50%. Not that it's the Cause, but treating it makes people better, and some have even recovered.

    Sorry if you have already been down this road, I can't remember anything lately. Mostly, I just want you to know I'll be thinking about you and I hope they don't find any blockages.

    Hope you start to feel better soon. Heart symptoms are so very disturbing and scary.

    Kelly
  12. Finch

    Finch Down With the Sickness

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    Muscle fatigue - YES!

    I've always known my muscles were fatigued - my heart muscle included. I'm very glad someone is finally studying this so intently.

    Koan and Victoria - I know exactly what you mean about not being able to move. For me, it happened often when I used to try to go to the grocery store by myself. What healthy person could understand the exhaustion that can come along with such an endeavor? Many times I would pull my car into the garage and just sit there. I don't know for how long. I could not move at all. Finally some force of will would get me out of the car. There was frozen food in the trunk that had to get into the freezer, after all.

    Other times I would crash onto the bed or the sofa. It could be after doing something as simple as changing the sheets on the bed. There I would be, thinking again and again about getting back up, but not being able to will my body to do it. Only the need to use the bathroom would finally get me up and moving again.

    Kelly - I am working with the infectious aspect of ME/CFS. In my case it's with chlamydia pneumoniae. I'm using a combined antibiotic protocol, along with supplements, to attempt to eradicate this pathogen from my system. It's a long and difficult process, but I feel I'm making some headway. I still have a very long way to go and don't know exactly how much improvement I'll be able to obtain, but I feel like I'm at least doing something. Cpn is known to be a pathogen that can make a home in any part of the body, the heart included.

    I've had a few periods during my 19-year ME/CFS experience when I've been able to actually exercise with little difficulty. These periods, which have lasted up to several months, have always been followed by sudden and severe crashes. For the past couple years, I have not been willing to even try to exercise, and I've remained fairly stable, although certainly not well. This is very frustrating to me, as I don't know whether I'll ever be able to become "fit" again, and I would so like to!

    Thank you, Cort, for the encouraging news.
  13. Cort

    Cort Phoenix Rising Founder

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    This inability to move I'll bet is different. I've met several people who describe a strange inability simply to move; its not necessarily a function of fatigue - its more like the brain is unable to pass the signals to the muscles to move. I think its probably found in people with a more advanced case of ME/CFS.

    There's a really interesting thread on this in the Symptoms forum

    http://forums.aboutmecfs.org/showthread.php?t=194
  14. Dolphin

    Dolphin Senior Member

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    Not sure I have the end energy to read all the messages in this thread at the moment. But I happened to read a report on a talk by Russell Lane, a UK neurologist, where he said his research found there was a peripheral compents to the fatigue, in some of the patients they studied.

    If one puts: "Lane RJ"[Author] "fatigue syndrome"
    in
    PubMed http://www.ncbi.nlm.nih.gov/sites/entrez
    one can see the abstracts to his research.

    Also a lot of the full texts can be accessed for free (follow green links).

    This doesn't say that the research the Lights are doing is wrong. It's just the way they're trying to interpret their findings may be wrong.
  15. Finch

    Finch Down With the Sickness

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    Yes, it's like I would keep thinking I was going to move, but nothing would happen. It wasn't like being paralyzed or anything. It wasn't scary, because I knew I would move eventually, and after some time I would slowly get moving again. It's just a very strange feeling if you let yourself think about it at the time. In a normal situation, like sitting in the car, it's not that you're thinking, "I'm just too tired to move." It's like you would normally get up and get out of the car, but just nothing moves and you just keep sitting there. Eventually the will wins out.

    It's really like everything else we do, though. Everything seems to require such extreme effort. That's why the results showing a CFS patient exercising mildly for 15 minutes comparing a healthy person to running a marathon is really an eye opener. I think we just get so used to everything being such an effort. We actually have to work hard to will ourselves to do even simple things (if we can do them at all). Healthy people who have not experienced this type of "fatigue" really can't have any idea what it's like.
  16. Aftermath

    Aftermath Guest

    Mycoplasma

    He was also absolutely convinced that mycoplasma was the cause of GWS.

    After some very convincing studies with long term doxy, it's pretty clear that this is not the case.
  17. Dolphin

    Dolphin Senior Member

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  18. oceanblue

    oceanblue Senior Member

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    Yes, this is extraordinary work potentially giving a whole new paradigm for fatigue in general as well as for this illness. Any idea if there is more work in the pipeline? The number in the published study are small (19 patients, complicated by some having FM, some not), particularly in the context of gene expression studies.

    This is some of the most exciting work I've seen in years, but I'd love to see the findings confirmed by larger more robust studies.
  19. CBS

    CBS Senior Member

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    As I recently stated on another thread, more work is on the way from Drs. Light, Light and Bateman. Alan and Kathy Light recently provided a preview of subsequent studies that are working their way towards publication at an educational meeting of OFFER Utah. Some of the interesting findings are biomarkers that differentiate between CFS and fibromyalgia (including a fibro marker that can identify patients without the need for an exercise challenge test) and a biomarker that can identify a sub-group of CFS patients.

    The Lights have a number of other markers they would like to test. The primary barrier to doing so is money. You can donate through http://www.offerutah.org/donations.htm (and yes, you can request that the funds go to support the Lights or to research in general - Drs. Bateman and Singh).
  20. Cort

    Cort Phoenix Rising Founder

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    Thanks CBS - I am so excited by their work :) Now to find that other thread...

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