The 12th Invest in ME Research Conference June, 2017, Part 2
MEMum presents the second article in a series of three about the recent 12th Invest In ME International Conference (IIMEC12) in London.
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Paraneoplastic Syndromes

Discussion in 'General ME/CFS Discussion' started by anciendaze, Mar 14, 2016.

  1. anciendaze

    anciendaze Senior Member

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    Moderator Note: This thread was split from Flash of insight: Viral Meningitis
    @Asa, @duncan

    Paul Cheney has repeatedly said he can't tell the difference between his patients with CFS and those with post-treatment Lyme disease. He has also said he and Ritchie Shoemaker, who treats people for responses to mycotoxins, trade patients. This sounds like an autoimmune problem triggered by external factors. These are not the only possibilities.

    Paraneoplastic syndromes may involve only a few cancer cells which can't be directly detected. It is the powerful immune response that gets attention. You may later find a cancer. I think this may have happened with Gilda Radner, who had a history of problems like bulimia, long before she was diagnosed with ovarian cancer too late for treatment to save her life.

    We have never gotten answers to questions concerning a relation between rare lymphomas and ME/CFS because everyone diagnosed with lymphoma is said never to have had CFS. Those patients not known to have developed lymphomas show levels of nagalase (α-N-acetylgalactosaminidase) comparable to cancer patients, which also could indicate autoimmune involvement.

    If either infection or neoplasms can trigger autoimmune responses so selective they only attack some molecular component of a particular class of receptors it is unlikely this will show up on an MRI or in typical pathological tissue examinations. This would bring the term encephalomyelitis into question. In the case I mentioned, there was no visible evidence of inflammation on MRIs, yet the term encephalitis is used because of dramatic effects on the brain apparent in EEGs, as well as the discovery of leukocytes in cerebrospinal fluid.

    In another disease where autoimmune response against postsynaptic neuromuscular junctions is known, myasthenia gravis, severe weakness is the result. Autoimmune responses can be highly specific or ridiculously broad, as happens in connective tissue disorders. We have not begun to exhaust the possibilities.

    Added: I've now reached the point in the book where treatment began to work, one part of this was Rituximab, still another indication of an autoimmune/neoplasm problem.

    Moderator Note: The following part of anciendaze's post was moved from another of his posts in the viral meningitis thread:
    -----
    On a different subject, which relates to the mention I made above of paraneoplastic syndromes, I started to search for connections between autoimmune diseases and cancers. There is a great deal of material on autoimmune disease as the result of cancer treatment, these being considered the lesser of two evils. This was not what I was looking for. I wanted to see how a preceding autoimmune disease affected incidence of diagnosed cancer.

    Anyone else who is interested in the association between particular autoimmune disorders and particular cancers may find this reference I turned up useful. Although causation is still a fairly large question, there is absolutely no doubt patients with various autoimmune diseases do experience higher rates of particular kinds of cancer. I suspect some "autoimmune diseases" will ultimately be reclassified as paraneoplastic. Common thinking may be to suggest that the autoimmune condition causes cancer, but it is equally plausible that the cancer causes the autoimmune response while remaining below current thresholds for detection as cancer per se.

    In terms of medical specializations there is a great distance between oncology and rheumatology. If there had been more communication I believe paraneoplastic diseases would have been discovered earlier.
     
    Last edited by a moderator: Mar 16, 2016
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  2. bel canto

    bel canto Senior Member

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    Yes, thanks, anciendaze for an interesting thread, and, particularly for the referenced article above!
     
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  3. Gingergrrl

    Gingergrrl Senior Member

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    Thank you so much @aciendaze for posting all of this info and I really hope to have the opportunity to chat with you about it! Ironically (before I explain my situation) Gilda Radner was my idol and hero growing up and I read her book, "It's always Something" at least 20x plus every other book written about her (3-4 others) and followed her story up until her death and beyond and the formation of "Gilda's Club" all over the world. I just adored her beyond words can express and feel like she is speaking to me through this thread (not in a crazy way LOL but it feels like a sign.)

    Am hoping to learn more from you as to why you felt she had a paraneoplastic syndrome (PNS)?

    I had some bloodwork sent to Mayo Clinic by my doctor including the paraneoplastic panel (PAVAL) and I am positive for two antibodies, Anti GAD65 Ab (which is still vague to me) and N-Type Calcium Channel Ab which is highly correlated to LEMS, small cell lung cancer (SCLC), and paraneoplastic syndromes. I will be having a pulmonary eval and see the Neuro later this week but they suspect I might have LEMS and I will need to have another lung cat scan (I had one in Oct 2015 which was perfectly clear.) They think the antibodies could be weakening my lungs (not sure if it is the neuromuscular junction but they attack the ion calcium channel?)

    You know from chatting with me before that I am the least scientific person on earth but have had some amazing friends from PR help me to understand these terms and what they might mean. My lung functioning is very poor on PFT tests (upper 60's or low 70's for restrictive disease) and I can no longer inhale a full breath. I used to be affected only standing/walking but now if I talk to much, I have burning lung pain and weakness (even if seated or lying down.)
    Am not asking you or anyone to diagnose me but would love to understand the paraneoplastic syndromes better and just printed out the article you linked (but have not read it yet.) We leave tomorrow to see the pulmonary doc and my doctor (it's a six hour drive) but it's worth it. They are suggesting IVIG or plasmapheresis to try to get rid of the antibody but that is all I know so far. Am not sure if they are recommending both treatments or just one and will be learning more.

    This is what I am wondering as well. Does the autoimmune disease cause cancer or does the cancer cause AI disease and where does the PNS fit in the equation? I have Hashimoto's and MCAS and am highly on the autoimmune side with no cold/flu or fever in over three years. It is so confusing and until two weeks ago, I didn't even know I had this antibody (or possible LEMS or lung cancer!) and was trying to rule out if I have small blood clots in my lungs b/c of an abnormal V/Q scan or possible pulmonary HTN (actually am still trying to rule those things out.)

    ETA: Myasthenia Gravis and MuSK antibody are negative and have been ruled out in my case.

    This book looks very interesting and am going to read the link, too, and maybe buy it.

    It seems like there is no communication between any specialities (at least in the US) and my care has been completely fragmented. I see a specialist for MCAS and also saw one for my severe mold exposure (both are phenomenal) but I literally tried for about six months to get them to speak with each other but could not get it to occur. At least my appts this week (pulmonary and autonomic/neuro who ran the antibody tests) are at the same hospital and they will be speaking and coordinating my care together plus they referred me to a neuromuscular doc. But my care back home has been completely fragmented which has not been to my benefit.

    Yes thank you so much @aciendaze and thank you @bel canto and to several other people who pointed out this thread to me or I would have completely missed it.
     
    Last edited: Mar 15, 2016
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  4. anciendaze

    anciendaze Senior Member

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    @Gingergrrl

    I do want to warn people that the story of that young woman and her family is pretty rugged, even though the outcome was remarkably good, considering the seriousness of the illness. It could easily have become tragic. For those stricken before NMDA-receptor autoimmunity was identified I'm sure it was. None of the treatments used on mental patients would have stopped the damage.

    I'm far from any kind of expert on paraneoplastic diseases. Although I knew there were overlaps between autoimmune diseases and some cancers in terms of test results, I had simply not heard the term paraneoplastic before the last few weeks. I was chasing something different when I ran across this.

    My wild-ass guess about Gilda Radner was due to noticing that ovarian cancer is one form that triggers powerful paraneoplastic immune responses. If this response actually controlled the cancer before it reached a late stage her strange problems even years earlier might have been related. Any rheumatologist will tell you about cases of autoimmune disease that develop over years. I'm still bothered by the question of how any competent doctor could miss a diagnosis of ovarian cancer so long.

    Now, on your test results, the GAD65 antibodies attack an enzyme called glutamic acid decarboxylase. It is part of the synthesis pathway for GABA (gamma-amino butyric acid), an important neurotransmitter. In more practical terms this can cause a wide range of mysterious problems that I'm sure your specialists will look for.

    That girl in the book had an autoimmune response to NMDA receptors, which are a special class of glutamate receptors, (and, yes, these are related in terms of common biosynthesis pathways, but quite different in specific function.) Based on that one case I'd say a paraneoplastic response targeting NMDA receptors can produce damn near anything in the way of symptoms. I have no idea what your GAD65 antibodies are doing, but I doubt it is good.

    The other find, the N-type Calcium Channel antibodies, should have considerable effects which might explain other problems you have had, particularly with circulation. This sounds like a real lead on all that has been going on. Doctors already use drugs called calcium channel blockers to affect this, and some conditions they treat sound like a few I recall you experiencing. I'm not about to tell you what they should or should not do. You seem to have made your way out of the diagnostic briar patch with test results that should guide further treatment. This looks pretty solid.

    Your results are more like what I was looking for when I ran into information about paraneoplastic syndromes. I have a friend who suffers from a rare channelopathy involving potassium channels, but doesn't have any identified genes for the problem. There is no question about the reality of his problem because provocative tests have nearly killed him, and there were good recordings kept and samples drawn when this happened. If he didn't inherit the problem, in the simple way, my next thought was that it could be the result of an autoimmune response targeting some molecule essential to the function of the channels in question. At present he may be the longest surviving patient with a particular combination of problems in the U.S. This makes him about 1 in 100,000,000, a "zebra" among "zebras".
     
  5. picante

    picante Senior Member

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  6. anciendaze

    anciendaze Senior Member

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    @picante

    They are not talking about myalgic encephalomyelitis, but a "real" disease which meets earlier definitions of inflammation of the brain and spinal cord. There are multiple kinds of encephalomyelitis, and some are progressive and lethal. I'm not sure there is any chronic encephalomyelitis accepted by the bulk of the medical profession. We need better terminology, which will probably arrive when we understand what's going on.
     
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  7. Gingergrrl

    Gingergrrl Senior Member

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    I have no doubt the story will be intense but it something that I would like to read some day (no time right now anyway!)

    I actually had not heard of the term paraneoplastic myself until 3-4 weeks ago when my new Neuro had me do the PAVAL test panel for Mayo. And even then I did not grasp what it was until my tests came back positive for two antibodies. I did not know of the connection between autoimmune disorders and cancers either. I feel like I am in a whole new world right now.

    Thank you and I understand in the sense that even though Gilda had access to the best docs, they misdiagnosed her until she was at the point of stage 4 ovarian cancer. They diagnosed everything under the sun but never ran the CA-125 tests or basic tests b/c her symptoms were "vague" (although just the stomach bloating and not being able to close her pants was a clue IMO.) Did she have autoimmune issues that signaled a PNS that I am mis-remembering (vs. that they just didn't diagnose her in time to potentially be saved?) I have not read her book in many years but just adored her beyond words.

    I think this test was actually separate from the PAVAL panel and I remain unclear if this one links to cancer vs. a wide array of other potential issues. The other anti-body n-type calcium channel Ab is the one highly linked to LEMS and small cell lung cancer. All they are telling me right now is that this test links to my dysautonomia (the GAD65) but another friend from PR pointed out that it could be messing with the smooth muscles/nerve conduction in my lungs and affecting my breathing (I am paraphrasing and this person said it much more scientifically!)

    I agree it is not good which is why they want me to do treatment to get rid of the antibodies (IVIG or plasmapharesis) but I will learn more later this week.

    My understanding is that I would *not want to take any kinds of calcium channel blockers b/c this antibody is already attacking my calcium channel. Do you understand it differently? Am very curious now! I feel like I am still very deep in the briar patch (to use your term!) b/c there were several things potentially wrong with my lungs/breathing (in addition to confirmed POTS and MCAS) before I even knew I had this antibody. And now I will have to undergo thorough cancer checks, especially on my lungs for SCLC.

    I remember chatting with you about your friend at the end of 2014 when I had pulmonary edema from IV saline and you were wondering if I could have the same issue as your friend (but my symptoms were very different.) Can your friend get the PAVAL blood test or other Mayo tests (or has he already done this?) Do his doctors think he has a paraneoplastic syndrome? My doctor is trying to sort out if I have LEMS, PNS, cancer or just have these antibodies. I now suspect the antibodies are the neuromuscular reason behind my lung weakness. I also feel like one of the zebras like your friend or like the black swan. Regular docs would have left me to die but at least now I have a solid lead to pursue.

    If this is too off track for the original thread, can we talk via PM? Can you remind me if you are in the US or UK (or elsewhere?) For the next three days I will only have iPhone access vs. computer so much harder for me to respond in detail but the timing of you posting all this is incredible for me and thank you @picante for starting this thread!
     
    Last edited by a moderator: Mar 16, 2016
  8. anciendaze

    anciendaze Senior Member

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    @Gingergrrl

    Important: I did not mean that you should be treated with calcium channel blockers. I was saying that doctors do have experience with the effects of manipulating calcium channel activity. This is much better than the situation where nobody knows what might happen if they intervene, and all they can do is "try something". Far too many of us have been in the latter situation.

    I'll be interested in hearing what you learn, and if you don't want everyone involved I will be happy to talk via PM. Just remember that I am not a doctor, more like an interpreter of medical language. From what I've already learned on the subject, it seems doctors trained prior to 2007 are not all that far ahead of us, while those trained after 2007 are still short of medical experience. We are all learning.
     
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  9. picante

    picante Senior Member

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    Dear GG, you are so welcome! I'll be interested in following your story, too. It's a radical new concept for me, but I think that's what we need more of for our community.

    I'm one of the population who got polio vaccines when they were contaminated with Simian Virus 40 (officially, 1955-1963). SV40 is associated with certain cancers. The virus has been making its way through the human population since, yet doctors rarely think to test tumors for SV40.

    I bring it up because it might tie in to the paraneoplastic syndromes.

    SV40 is well known in medical science. If I understand right, it is used to transfect cell lines (including human cell lines) and "immortalize" them for use in cancer research. Although that doesn't keep the CDC and Co. from issuing "reassurances" that SV40 is "not known" to cause cancer in humans.

    Since paraneoplastic syndromes are a different (but related) topic, I'm wondering if perhaps it deserves its own thread. Please tag me if you start one. Or I suppose we could ask a mod to split this thread just after my post #28 from last night. What makes sense to you?
     
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  10. Gingergrrl

    Gingergrrl Senior Member

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    @anciendaze Thank you for clarifying and I appreciate it.

    I would love to chat further via PM but also happy to continue sharing here if this info is helpful for anyone else as @picante said in the post below (which I am going to respond to next!) I love that you refer to yourself as an "interpreter of medical language" and that is exactly what I need. Can I hire you LOL? I guess b/c the hospital/clinics where I am being treated is a combination of docs trained before and after 2007, I have the best of both worlds!
     
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  11. Gingergrrl

    Gingergrrl Senior Member

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    @picante thank you so much for saying that and I really appreciate that. If my story can help someone else, it makes a tiny piece of the suffering worth it.

    Unfortunately I am not familiar with this at all or how it ties in with the PNS's but would love to learn more.

    We are literally leaving in about 30 min on our trip to the medical center for my appts tomorrow (six hour car ride) and I will only have iPhone access and no computer. So I cannot start a new thread but am happy with whatever you and the moderators decide to do with this one (split it or leave it as one.) If it does get split, can you tag me into the new one? Thank you in advance!
     
  12. anciendaze

    anciendaze Senior Member

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    @picante

    Just to keep some perspective I want to point out that SV40 in vaccines is far from the only carcinogenic virus to which humans are exposed.

    We now know that bovine leukemia virus (BLV) does infect humans, and is associated with breast cancers. We probably don't know many other associations simply because damn near everyone has been exposed to cow's milk or beef, if not living infected cattle. If it infects human breast tissue it can probably be transmitted to nursing infants. (Since my maternal grandmother kept a cow for milk, and did not pasteurize the milk, my mother could well have been infected as a child, and passed this to me.) Even when the virus has been destroyed, by pasteurization, the molecular components remain, which makes it hard to test people. For a long time it was assumed that anti-BLV antibodies in humans were the result of response to those components, not active viral infections. It is still hard to separate evidence of infection from antibodies to dairy products.

    Likewise the murine leukemia viruses (MLV) that caused such a flap can be found in mouse droppings without any special effort. Dust from mouse droppings gets inhaled, and sometimes this causes epidemics, as happened with hantavirus, though that is not a retrovirus. If the chain of cause and effect is longer, the association with cancers will be much harder to identify. MLV will infect human immune cells in vitro,and these cells do move from the surface of the lungs to lymph nodes. The makes it possible for MLV to infect human immune systems without producing extensive viremia. This must have been going on for a long time, and, for most healthy people, the infection remains under control. What happens when immune function weakens is another question.

    Some cancers have a strong association with particular genes, and we are still tracking many patterns of inheritance in genomes. I've long had a dispute with old-style oncologists over thresholds for detecting cancers. As far as I can see, there is an effort to reassure people that they do not have the dreaded disease itself, but only some "precancerous" cells. The resulting definition strikes me as a tautology: you can't have cancer until we detect it and say it is cancer. This has had a serious impact on efforts at early detection and prevention.

    Even if people lived in sterile bubbles they would still have to cope with many HERVs transmitted along with their genes. Some envelope proteins cause immunosuppression all by themselves, and it is not difficult to find intact envelope genes in HERVs, nor is it hard to find evidence of transcribed HERVs or even reverse transcription. Virtually every HERV appears to have been introduced by an exogenous retrovirus associated with cancer, at least in other species. It may have happened in the distant past, or it may still be an ongoing process, but there is no question humans are infested with things that can cause cancer. HERV-Fc1 is much closer to intact than the fragments assumed to recombine to produce XMRV. The "patch" required to fix known defects is tiny, and there are many such sequences available in other HERVs. An experiment to do this might be possible, even easy, but the danger of resurrecting a human pathogen capable of spreading cancer would mean it would have to be carried out under extraordinarily tight controls.

    My own outsider's view is that there is real evidence that isolated cancer cells do turn up many times in life, but are usually eliminated by healthy immune systems before they are identified as neoplasms. This means I should have anticipated paraneoplastic syndromes, but I was busy trying to separate papers on autoimmune disease from the enormous confusion created by actual cancer and treatment. My preconception that these were separate and distinct problems blinded me.
     
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  13. Gingergrrl

    Gingergrrl Senior Member

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    That is very interesting and I agree. I read your article last night that you linked and it has great statistics and info on LEMS, PNS and lung cancer. I also just ordered the book, "The girl on the 6th floor" on Amazon. I know it is completely different than my case but looks very interesting to me. Am leaving in a few minutes but thank you again!
     
  14. halcyon

    halcyon Senior Member

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    There may be evidence that ERVs are crucial to immune response too though and they are mobilized as part of the cell danger response.
     
  15. jimells

    jimells Senior Member

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    If doctors were paid for their time like any other professional, instead of by procedure code, these specialists would suddenly find the time to talk to each other. Maybe they would even talk to patients on the telephone.

    Hoping you don't suffer too much during your road trip.
     
    Last edited: Mar 16, 2016
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  16. bel canto

    bel canto Senior Member

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    The whole concept of paraneoplastic opens up a lot of questions. The severe ones that attack the cerebellum or the muscles have been looked at and antibodies identified. But how many others are out there that are not as disabling and therefore not identified?

    If someone is diagnosed with a cancer, that would likely drown out concerns about other symptoms that have occurred prior to that time. If someone is never diagnosed with a cancer, but has symptoms arising from their immune system - which successfully battled a cancer, but inadvertently has done damage somewhere else - it would probably never be diagnosed.

    Just speculation.
     
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  17. liverock

    liverock Senior Member

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    @Gingergrrl,

    This is from a man who has been diagnosed with N-Type Calcium Channel Ab and GAD 65 antibodies

    He seems to have all the symptoms of ME, overall muscle fatigue similar to flu like symptoms as well as POTS and small fiber neuropathy, however nobody can give him a definite diagnosis. He appears to have gut (GAD 65) problems as well. Really confirms @anciendaze thoughts on this particular N Type Calcium antibody and autoimmunity diseases.

    https://www.inspire.com/groups/agmd-gi-motility/discussion/paraneoplatic-calcium-channel-n-type-ab/
     
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  18. anciendaze

    anciendaze Senior Member

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  19. Sushi

    Sushi Senior Member Albuquerque

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    The quote below gets blocked by a sign-in page pretty fast. I managed to copy it for those who can't see it.
     
  20. Gingergrrl

    Gingergrrl Senior Member

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    Thank you guys (every single one of you who is helping me with this) and I have been in appts and tests all day with another full day tomorrow and we are extending our stay for an additional night. I can't post any details right now, it's way too difficult on my iPhone but will once we get home on Sat night or Sun.

    Am so appreciative of Stanford who is figuring all this out and if this treatment ends up working (long term) it will save my life.
     
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