Choline on the Brain? A Guide to Choline in Chronic Fatigue Syndrome
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Lecture by Dr Montoya from Feb. 2018, partly on antiviral treatment

Discussion in 'Antivirals, Antibiotics and Immune Modulators' started by Wonkmonk, Mar 4, 2018.

  1. Wonkmonk

    Wonkmonk Senior Member

    Sorry for posting this in the third place, but I really think this is interesting and those doing antivirals might not read the Rituximab threads and probably miss this.

    Very intersting lecture by Dr Montoya. Much of it is on antiviral treatment. Among the many key takeaways:
    - Antiviral treatment must be done over a VERY long time, according to Dr Montoya AT LEAST 5 years (quoted verbatim) -- after 46:15 (cc: @Hip)
    - Combination treatment of antivirals and anti-inflammatory drugs is probably warranted -- after 49:50
    - Valgancyclovir side effects were studied in cancer and transplantation patients and may therefore be overstated and the drug may be less dangerous than thought in otherwise "healthy" CFS patients -- after 56:15 (cc: @Learner1)
    - Dr Montoya's team is lobbying hard to have authorities drop graded-excercise therapy from treatment recommendations, but has not succeeded everywhere so far -- after 57:50
    - His team is currently taking a hard look at a drug called Tofacitinib, which has very broad anti-inflammatory action, and wants to do a trial soon -- after 59:25

    As a side note, it's impressive how Dr Montoya deals with the questions and what a friendly, compassionate person he appears to be. He seems to really care about CFS patients and their problems.

    CFSNZ, pibee, ukxmrv and 16 others like this.
  2. Hip

    Hip Senior Member

    Thanks for tagging me on this. It's certainly true that you need more than 6 months antiviral treatment (with Valtrex or Valcyte) for the full benefits to appear. If you look at Dr Martin Lerner's clinical trials of Valtrex and Valcyte for herpesvirus-associated ME/CFS (see the tables in this post), you see that patients slowly improve (as measured by Energy Index Point Score), taking 1 to 2 years for the benefits to fully manifest.

    Taking antivirals for longer than two years did not further improve the ME/CFS symptoms much (most the improvements are obtained in the first 2 years); however, such longer treatment might well help better clear any lingering infection, conceivably making it more likely that your ME/CFS will not return when you finally stop taking the antivirals.

    Note that the five years of antivirals that Prof Montoya talks about in the video refers to the time it takes for natural killer cell functioning to return to normal (rather than for symptomatic improvements to occur):

    In case anyone prefers to read the video transcript rather than watch the video, I copied the full transcript here:
    Thank you for having me here-- more importantly for having ME/CFS among the topics for the library.

    I don't see any other disease that has humbled me the most, has terrified me the most, and at the same time has propelled me the most to try to find answers-- to seek answers.

    What I would like to do tonight is present an example of a case of a patient, that we just saw literally this week.

    And it's just one example of many of the million and more Americans-- probably way more than a million Americans-- a million people worldwide who are presenting with this.

    This is just an illustration of how this terrible disease continues to strike humans.

    I'm trying to avoid some personal information, but she gave me permission to do this.

    Young, healthy, active American woman who developed full-blown chronic fatigue syndrome in 2013.

    She was born in the Midwest-- no health problems growing up, always physically active, and at the same time academically accomplished.

    Outdoor lifestyle, long, intense hiking trips-- she will take that Pacific Trail from Northern Mexico all the way to South Canada, and do that in one trip-- average hiking distance 50 miles a day.

    Full time job as an environmental engineer.

    Happily married to the most beautiful guy you can see as a husband, am example for many of us.

    Denies a history of depression or of any other psychological problems.

    This is one of the most striking things with this illness.

    And those who still don't believe in the illness don't see this, how healthy and active people were before the illness.

    And one of the main findings that led me as a physician to see that there was no possibility that these patients were faking an illness when they had this life.

    In 2013, during one of her trips, she developed classic herpes zoster.

    This is the same virus as chicken pox that people usually get in childhood, and is the same virus that later in life can get manifested with what we call zoster.

    Zoster is very classic, because you have those areas that we call the vesicular, and they tend to have these what we call radicular distribution.

    In this case it was a V1 ophthalmic branch.

    An ophthalmologist has to see these patients to make sure that the eye is not involved.

    And it can lead to serious problems in the eye.

    And she had it right there in where you see in the forehead on the left side and also the scalp.

    We don't have pictures of the scalp, but this is classic zoster.

    It was so classic that she received acyclovir with resolution of the pain, and one of the feared complications of this infection is that the patients may go on for decades with their horrible pain.

    And she did not have that-- lucky.

    However-- why is it that some will have this infection, will resolve it, and they will go back to normal, and others will have, like in this case, followed by chronic fatigue syndrome? Something went, according to her, wrong that she had never faced in her life-- extreme fatigue, limitation for her normal physical activities weeks after the herpes zoster event.

    Unable to walk for a few blocks without feeling extremely exhausted.

    She had to lie down in bed.

    Even normal events like showering, walking to groceries, became taxing and were exhausting for her.

    Even grooming her hair.

    She was trying to push forward in her daily activities.

    And who will not do this in desperation? She felt that she will have more exhaustion and she will be crushing even further.

    She also noticed significant cognitive decline for someone who was so academically accomplished, with less ability to perform readings, writing emails, significant [INAUDIBLE] finding difficulties, and associated memory loss.

    And I think that- in ME/CFS- the other thing is that it's a disease for compassion, but also for great clinical abilities.

    You really-- and listening to the patient.

    There is no way that you can, as you are seeing this unfolding, that you're going to say that this is the usual thing of somebody getting tired.

    2013-14, energy level continued to decline.

    And this is a nightmare that many patients go through.

    They visit providers and they're told that they have depression-- that they need to see a counselor, that it's something that is psychological.

    Very low levels of energy-- she had to quit job.

    Unable to engage in other physical activities-- basic life, and also the cognitive was taking her more downhill.

    In 2015, this is not infrequent, patients go a major clinic and many other places for an answer.

    And she did not have anything in terms of tick-borne diseases.

    It was attempting to say that she could have a tick-borne disease because of her hiking exposures.

    However, she did find other physicians who gave her multiple courses of IV an oral antibiotics which make her sicker, because she had side effects on the antibiotics-- diarrhea, more fatigue, and left her worse.

    She feels that the antibiotics did that-- no significant improvement.

    2017 and 18, she establishes care with a provider who thought that maybe there was something on that herpes zoster episode and it starts ongoing suppressive valacyclovir along with other meds like trazadone, multi-vitamins, and gabapentin.

    And since then, since September of 2017, for the first time she sees that, consistently, she is starting to get slight increase in her physical function and cognitive.

    She's now able to write e-mails and read.

    And we just saw her now, so I don't have an update of what happened after we see her, but she decided to come for clinical care and participation in our research studies.

    And that has been initiated.

    But this is not an unusual study of someone who has an entire normal life and there is a major event that can be, in this case, infection.

    But we know of patients who have had trauma, surgery, head trauma, pregnancy.

    And if one tries to-- what is behind? What is the commonality? What is the common denominator there? It's hard to ignore that it could be an immune response, because when you have surgery, when you have trauma, you trigger immune responses and the same thing with, obviously, infection-- pregnancy, major immune systems, also shift It's a serious issue.

    It's a test for human mankind compassion and kindness, because these patients go into such a desperate state that some of them take their lives.

    And this is a study in a relatively small sample size from Lenny Jason, who is an outstanding ME/CFS researcher.

    And he points out that there might be also issues of these patients with ME/CFS dying earlier.

    So if they're in the general population, most patients, more individuals die around 73.5 years of age.

    ME/CFS patients appear to that earlier, have cardiovascular related events earlier, suicide earlier, cancer-related earlier, He acknowledges that this needs to be validated with a larger sample size, which was done in the UK with this Lancet study, where they did a group of CFS patients in a larger sample size.

    Unfortunately, they did have 2,147 cases, but the period of observation was too short-- seven years.

    Despite that they period of observation was shorter, they did find increased suicide-specific mortality in these patients.

    And I cannot think how they will not at least think about that.

    And we have lost, sadly, some of our patients where hope could not reach them.

    So this is a serious issue and has potentially lethal consequences.

    I think that one of the biggest mistakes made by modern medicine is to have arrived to the conclusion that diseases like ME/CFS, fibromyalgia, Gulf War illness, chronic Lyme disease are a creation of the patients imagination.

    But these historical mistakes made by many official government agencies and mainstream medical associations has started to be mended by what has finally taken place in the way of February 10, 2015, when the Institute of Medicine came out with the report where, clearly, after reviewing 9,000 of articles or plus it was concluded that this illness was real and needed to be researched.

    And after Ron Davis, present here in the audience, was one of the members of this group.

    So this is one of the most respectable scientific organisms concluding that there was no question that there was scientific validity and biological validity behind this illness.

    And that has led to other organisms like NIH, and FDA, and CDC to really rally behind this idea of getting this solved.

    For practitioners, I think this has made a big difference, or can make a big difference, because one of the challenges with this illness as a practicing physician is that you are given very limited amount of time to really see the patient.

    And they have a history of five to 10 years, and you have to do that in less than an hour.

    And what this IOM work did very nicely is to simplify the way that you can arrive at the diagnosis, by basically asking five questions.

    The first one is the fatigue.

    And if the fatigue is not alleviated by rest, if the fatigue really substantially decreases that person's capacity to do work, education, social by 50% or more-- so a significant impact in their lives that doesn't go away by rest-- for more than six months, that's one criteria.

    The second, unrefreshing sleep.

    It's fascinating when you hear when you're listening to these patients, they will tell you that they do not wake up fresh no matter what they did.

    They have the issue that their sleep that we all look at as that restorative process that we all, as human beings should be entitled to, it doesn't happen regardless of how long they sleep.

    So that's a second cardinal feature of this illness.

    And the third is that thing of when they push beyond-- and the threshold of what constitutes too much for each patient is different-- they crash.

    And it's what is described as post-exertional malaise.

    And in internal medicine it's a whole fascinating world of many diseases that have been nicely described by centuries of good clinical observations, and research, and laboratory work.

    There is no other disease with these three features.

    There is no other illness that have those three features.

    So IOM in a fantastic way-- fascinating way-- arrived to this conclusion.

    And when we apply this definition to every patient we see new-- and we did a study and we went back to all the patients that we have seen, and applied this definition against the old definitions-- we find that it works.

    So this is really a nice, important, practical tool.

    that hopefully facilitates that patients like the one that I showed you-- it took her five years to arrive to the diagnosis of CFS-- can be told you have CFS six months later, or a year later, and not five years later.

    And some patients have gone with this issue for decades of not being diagnosed properly.

    And the other two is you ask if they have cognitive issues like that patient that I showed you, or orthostatic intolerance issues.

    And if they have the first three plus either of the cognitive or orthostatic intolerance, they have chronic fatigue syndrome.

    So I think this is extremely helpful for practitioners and for patients to be diagnosed earlier.

    That this is a real illness has been editorialized by Tony Komaroff, who has been one of the most active researchers and witnesses of this illness for 35 years plus.

    And he titled this perfectly in this very prominent Internal Medicine Journal, that this is a real illness.

    And no question that if one wants to throw the argument of economic impact, that for all angles that you see from the productive years that young patients lose, the many amounts of medical care that goes into their expenditures, that many people around them have to take care of them that lose that ability also to be in productive hours, the amount of money that is lost, for an illness that by now should be understood and should be having effective treatments is significant.

    Four major NIH grants were awarded in 2017 for this illness.

    That's a welcome addition to this.

    One for Cornell, one at Columbia-- we are part of some of the Columbia work.

    And at the Jackson Laboratory there is a data center that will be coordinating all data from the North Carolina site that is famous for statistical work.

    So I think that is helpful to have at least that fresh air coming in the way of findings coming from the NIH.

    Probably the process for deciding to whom the funding goes needs to be changed or fixed, but we don't have time to go over how that went.

    There are thousands of papers that had been published showing objective abnormalities.

    There is no question that if you do exercise testing in these patients and tilt table you will see abnormalities.

    Natural killer cells continue to be a common theme.

    It has become that every time that we have a new patient here at Stanford, we do the natural killer cells, and at least 30% of them have significantly low natural killer cells.

    And that's an important argument of reflecting why we do certain things in terms of management and treatment.

    Natural killer cells were placed by nature in humans to defend against tumors and viruses.

    And they have been really well conventional medicine studies showing that if someone does not have natural killer cells, they have really bad herpesviruses infections.

    The whole literature on that area is well documented.

    And CFS patients happen to frequently have low natural killer cells.

    And we have some of our patients who have no natural killer cell activity.

    So there is something that's a clue.

    And we use that observation to emphasize the potential role of viruses triggering the illness-- like the patient that I showed you-- or viruses perpetuating the illnesses, especially herpesviruses.

    There is no question immunological abnormalities that have been reported, metabolic microbiome, brain imaging studies-- obstacles for why if all this research has been done, and we have not arrived to a question, include the fact that this is really a tough disease.

    It's not a disease for an average physician, for mediocre physicians.

    This is a disease for really tough ones who like to take a challenge, because patients will come to you with years of illnesses, and also will come to you with many complaints from different systems.

    So if someone comes with shortness of breath and they have more shortness of breath if they walk, they get even more shortness of breath when they lay down.

    And you see their big veins here.

    And you hear an extra third heart sound.

    And the legs are swollen.

    It's so easy to say that patient has classic heart failure.

    But this patient will not present with anything classic, they will have that story, and some other patient will have a different story.

    So you really have to be able to zoom in and out as you are listening to the details to be able to say there might be a unifying process here underlying these various, different presentations.

    So that might be one obstacle.

    And it's that patient who clearly have the zoster and follow the chronic fatigue syndrome-- should I take that patient different than the one that had mono or EVB as their answer, or should that be different than the one that has CFS after a trauma? So it's complex, but that should not deter us to do the studies.

    But it could be one of the reasons it has been hard to conquer.

    The lack of standardization in research methods is significant.

    So when you see studies it's hard to find that the research methods align to what you should be doing.

    Sample size is big.

    I'll show you an example.

    We were fortunate with that study that we do with cytokines, but, obviously, partly of why we were successful has to do with the people we associated with, but also with the fact that we had a sample size of 200 patients and 400 healthy controls, and allow us to see something that was not seen before.

    That it became obvious by the data that we were seeing, we didn't have to force it.

    And then the technology, obviously.

    There were, in the 1800s, people dropping dead in London with what we know today is cholera.

    But back then, it was not any idea that that's what was happening.

    And only when principles of epidemiology and a microscope were used that it became obvious that was viral cholera.

    So it is possible also that we have not had that kind of technology for so many years-- for decades.

    But now, it could get us closer to what this illness truly is.

    And so, infection is likely to be one of the big ones.

    10% of patients who develop acute EBV, Q fever, West Nile virus, [INAUDIBLE],, zoster virus are going to have CFS after that event.

    And many patients will tell you, yes, I had that infection, and that's when my CFS began.

    We got involved in a very timid way.

    We observed-- I will always remember my first patient February 2004, who came with big lymph nodes and a lot of herpesviruses.

    I can only claim that I was attentive to what they were telling me-- the patient was saying.

    I was very familiar with antivirals, because I used them a lot in cancer and transplant patients in that patient population.

    If a physician could have a malpractice lawsuit if they don't use antivirals, because they will die of this.

    So I was very familiar with that.

    And I used that drug, and the patient, months later, my fatigue is gone and all that stuff.

    So I did listen to that And it started in a very timid way-- very low-key way-- in 2004.

    Then we went full-blown, and did a randomized, double-blind, placebo-controlled clinical trial showing that there was a benefit, even though the sample size was small.

    And then we got an anonymous donor in 2009 that really expedited things for us, where we had been able to put together infectious diseases, neurology, neuroradiology, GI, cardiology, immunology, genetics, bioengineering, and the human immune monitoring center.

    So it's only possible because it was catalyzed by this funding that came from this anonymous donor.

    And the group has grown significantly.

    And we have the immune center, we have the HLA and blood bank, we have neuroradiology, neuropathology.

    We have now just started the brain bank.

    But I hope that the brain bank doesn't work-- that that study, that we don't ever need to get any brain from any CFS patient.

    We are now approaching the microbiome and the nutrition with Chris Gardner.

    Cardiology, bioengineering and infectious diseases, bioinformatics-- bioinformatics is huge because you get this massive amount of data, and you have to have someone who will help you with the processing of that information.

    The studies include longitudinal studies following patients over the long-term, and includes cross-sectional study.

    And for that, we take advantage of the sample size as I mentioned.

    So this cohort of 200 patients and 400 healthy controls, they have undergone cytokines.

    We have issues with the gene expression, so we're going to redo the study of the gene expression.

    We were very unhappy with the data.

    There were serious issues in that data.

    We are excited waiting for the CyTOF.

    It's a specialized test of the immune system.

    And we have finalized the curation of the data.

    It's a lot of data.

    It's like 600 million data points for the entire study.

    And the HLA data just came up, and it's positive.

    So I'll now mention briefly about that.

    And we have some studies looking at the electrical activity of the brain-- the anatomy-- and the cardiac endothelial function.

    So all these things are moving forward, and we are very excited about that.

    One study that was positive since the last time I spoke here is the MRI-DTI study.

    So in a small exploratory study we found that the right anterior arcuate fasiculus in patients was increased in certain areas compared to controls.

    And the same thing with the right inferior longitudinal fasiculus.

    These are bandos-- they are fibers that connect one area of the brain with another.

    We were so happy when we saw this, and we kept going back to the data.

    The journal that publish this, Radiology, is tough.

    So we already were tough with ourselves, they were even tougher with us.

    But because we have been tough with ourselves, we were able to publish it relatively soon.

    And what is even more fascinating, the areas at the cortex that these bandos, these fibers, touch in the cortex of the brain, they are thicker.

    So something on the fibers, something on the areas that they touch-- and also, they white matter was reduced in CFS patients.

    So this is the arcuate fasiculus, and you can see it connecting here on the temporal lobe.

    And it's found that it's much expanded here in CFS patients, and when he goes all the way to the frontal lobe.

    And the areas that it touches are thicker, here and here.

    And this is the inferior longitudinal fasiculus .

    Our hope is that this can become a biomarker.

    You can see here the right arcuate fasiculus and the longitudinal fasiculus in yellow.

    We are right now in the midst of trying to validate this finding.

    And it has been so sad that everything time we had gone to the NIH despite that we have that publication, we have the data, we have everything right, we had the right team, there's always been an excuse about the funding for the study.

    But we decided to leave that behind.

    And we have been seeking the funding.

    And it looks like we will be able, hopefully, within a year and a half, to see if we can tell the world, we have something in the brain of these patients that objectively shows that there is this abnormality in the right arcuate fasiculus.

    The fascinating thing is that he has to do with areas of processing for language and word finding, which is exactly what the patient will complain.

    So we are very hopeful about this biomarker.

    And the thing you can trust is that we will continue to apply the most rigor, that if we find something it will be real.

    And we are not afraid to say, we didn't find it, or that we find the wrong things.

    So stay tuned for this potential biomarker.

    These are the areas of the brain that the cortex are thicker, where these fibers are touching the area.

    And these are two separate techniques, and they find something that is abnormal in the same place.

    So it's even more hopeful.

    This is what is called they receiving operating characteristic curve, where you want to have very low false positives, and you're going to have a lot of true positives.

    And for this test, if we show that it's the biomarker has been waited for in the brain, it performs extremely well for a clinical test.

    So we're waiting to see what happens.

    This is the study that we did with cytokines.

    And the idea was to see if we measure many cytokines at the same times-- cytokines, as you know, are these small molecules that the immune system uses to communicate one cell with the other.

    And you can find them easily in blood.

    The one thing that we did on purpose is that we needed to get a large sample size, so we got close to 200 cases and close to 400 healthy controls, and we paired by them by age so that age was absolutely the same.

    And the sex distribution, it was the same.

    77% here, 77% here.

    We have a little bit of an imbalance in the ethnicity, where we end up having more Caucasians in the CFS group than in the control group, but, statistically, you can't control for that, to make sure that that will not explain the differences.

    And you can see here that most of our patients for sure have the ION criteria, since many of them will have close to 96% impaired memory, unrefreshing sleep, 97%, post-exertional malaise, 97%.

    So they were truly CFS patients without any question.

    And the first thing is that we were disappointed because we found very little differences between the two groups.

    You know, you invest all this effort, and money, and resources, and you only find that one cytokine transforming growth factor beta was elevated without any question.

    So when we give you findings, they are without any question.

    We spend a lot of time making sure that they are real.

    And then their resistance was lower.

    Now, they transforming growth factor can be very important.

    So that cytokine has been found elevated in CFS patients in at least five previous studies.

    And it's a cytokine that, for example, tries to decrease inflammation, but when too much inflammation is going, it does the opposite.

    It increases inflammation.

    In animal models in early phases of inflammatory responses, DFBETA along with IL-10 placates inflammation, but when the process goes too far it becomes detrimental.

    DFBETA also, unfortunately, has been found to promote lymphoma development and worsening lymphoma.

    And patients with CFS have a heightened risk of lymphoma.

    So we are wondering if this is the biological link between the propensity that patients with CFS have to lymphoma with that malignancy.

    And then, DFBETA is also frequently found in Ehlers-Danlos.

    And patients with Ehlers-Danlos or hypermobility, they have lots of patients with CFS.

    So it may be also there.

    We are not certain whether this should be the therapeutic target, but we are thinking in clever ways that maybe have five to 10 patients, inhibitor DFBETA, and see the clinical response.

    But it could be a therapeutic target in these patients.

    What we were really astonished by-- and I will never forget that morning in March in California when we saw this data.

    We did have it as a check-box.

    We said, we have to check whether duration is important, whether severity is important.

    This data literally spoke to us.

    We were not expecting it.

    We knew we had to do the analysis, but we did not know that it was going to come so clear.

    So if you see in the x-axis you have four groups of patients.

    The first is the control.

    Then you have patients with CFS with mild, moderate, and severe disease.

    And in the y-axis you have the level of the cytokine.

    And what was striking was that seven of those cytokines follow in an upward trend the severity of the illness.

    The milds tend to have on the low side-- the milds will be in the middle, and the severes will have the high.

    That was that upward trend that was so striking to us.

    Some of them were statistically significant different than the controls in those two groups, like IL-13 severe group, leptin in the other direction for the mild group.

    And when you have this, you have to be careful that you don't get too excited, and that you don't apply things that are not there.

    So we were heavily paralyzed by our statisticians.

    And we asked them a simple question, which of these upward trends are significant? And statistically significant, that doesn't mean that it's biological is [INAUDIBLE] relevant, but it's a little bit-- it gets you closer to biological truth.

    And after heavy penalization, they found 17 cytokines.

    We found 17 cytokines in which the upward trend was clearly significant.

    And, obviously, the next stop is to sit down in the dark alone and think about what this could mean.

    And it became obvious that 13 of those 17 cytokines were pro-inflammatory.

    They were promoting inflammation.

    They were making more of the things that give pain to patients, and makes them feel sick.

    Many patients will come to you and say, I feel my brain inflamed.

    I see that my whole body is inflamed.

    And things like, for example, interferon gamma-- that is used to fight viral infections-- IL-17, leptin, get a [INAUDIBLE] factor [INAUDIBLE] macrophage [INAUDIBLE] factor-- all these cytokines are worsening inflammation.

    And the more severe that disease, the higher those cytokines are.

    And that association, in science, you cannot necessarily say these cytokines are causing chronic fatigue syndrome, because chronic fatigue syndrome might simply be the disease that is causing the increase in cytokine.

    But it's very striking the association with the severity.

    And that has led us to propose that it might be responsible-- if we are correct-- that chronic fatigue syndrome is a cytokine storm that goes chronic.

    There is good evidence of acute cytokine storms doing real harm to patients.

    The most recent thing that is novel-- that is all in the new literature in medicine-- is with the use of these checkpoint inhibitors for cancer, or CAR T-cells, where you take the T cells of a patient and you engineer the T cell off the patient to attack it's own B-cells, specifically the CD9 receptor in the B-cells which have cancer.

    And those T-cells from these patients are taught to kill the B-cells from [INAUDIBLE] patients are given back to the patients, and they attacked that tumors.

    And there are beautiful responses in lymphoma and leukemia, especially lymphoblastic leukemia, with these CAR T-cells.

    Those patients have these horrible what is called cytokine storms, where these cytokines that I showed you cause fever, and confusion, and fever hypotension, hypoxia, long respiratory problems, inflammation of the brain.

    So what we are proposing here is a model of a disease where those very same cytokines that acutely can cause horrible things to patients may be doing this in an ongoing, chronic, unabated fashion to CFS patients.

    If you take those 17 cytokines and you start the group them by what they could do, it's very tempting to see, for example, CCL11, IL-4.

    IL-5, IL-13.

    And when you go and check, what are the main things that they do humans? Very similar-- eosinophil trafficking, IGE, eosinophil growth, differentiation.

    So that commonality in those cytokines is all these hypersensitivity that the patients have to drugs, to toxins, to environmental stimulants.

    It's really tough for patients, because, for many of them, anything will send them into a crash.

    Anything-- even breathing, or anything.

    And it could be that is based on this group of cytokines that produce that biological effect.

    The other way to group them is by the induction of inflammatory states that had to do with the innate immunity or adaptive immunity.

    Or some of them will do innate and adaptive.

    Unadaptive, adaptive.

    Innate unadaptive.

    And when you close your eyes and you see this data, you say, no wonder why this patient has been so sick for so long, and no wonder why we have not been able to come up with an answer for them.

    But also, it warns us about doing interventions for the immune system that are narrow.

    I know that we are all disappointed with the rituximab data that just is about to come up in the form of publication.

    But I think that there is now enough people talking about it that I feel comfortable to say that it was negative.

    And we were very hopeful for that trial in Norway.

    And I think this explains it, because the rituximab is just a CD20 B-cell blocker.

    And B-cell is just one component of the adaptive immunity, and has nothing to do with innate immunities.

    So you are just tackling one component-- very narrow component.

    Another example of cytokine inhibition for patients with chronic fatigue syndrome that is not likely to work, and it showed that it did not work, was this cytokine inhibition with Anti-L1.

    This is a cytokine against an interlocking one.

    And it didn't work.

    It was [INAUDIBLE] only for four weeks, so that was another mistake, or another problem.

    For CFS you have to intervene years not weeks.

    And it was not effective.

    But it's not a surprise, it was just targeting one thing.

    To illustrate the complexity, this is a study out of Columbia that our group was part of, where a combination of metagenomics and cytokines-- so gut microbiome and cytokines were put together.

    And when you analyze three axises of data that are complex on their own, and you do what is called network analysis-- like a topological analysis of gut microbiome, cytokines, and metabolomics in blood, you can separate patients who have controls here.

    You could have CFS patients without IBS and CFS patients with IBS.

    So the thing that is hinted in is, sample sizes, complex technology, interaction as a way to move forward-- this illness, hopefully to effective treatments.

    I mentioned to you the work that we did with the cytokines.

    And I'm happy to report that we have HLA findings.

    We have HLAs that increase the likelihood of patients having CFS, HLAs that increase the likelihood of patients having severe CFS, and HLS that increase the likelihood of having mild CFS.

    So that thing about, why me, or why I end up in bed, and that other patient is still functioning, may be explained through genetics.

    And one of the things that we have decided in our group is to reach out to Ron and to Ron's group for that publication, because we really need to have the input on that area.

    But we have, in that same patient population of the 200 patients 400 healthy controls, HLA predisposition for the illness.

    What we do in the clinic-- this research-- in each patient we get complete CBC, comprehensive metabolic panel, thyroid function tests, sed rate, and we do herpes-- we emphasize herpes-- and NK cell function.

    Often, again, these patients have very low NK cell function.

    And depending on the epidemiology, we go into these tests.

    There are some patients that will have ME/CFS, and it will have something unique, and this is CFS leak.

    So pay attention to that possibility.

    They will tell you headaches are prominent and headaches when they stand up.

    And they have the orthostatic symptoms very prominent.

    So we have a student from Germany who came to see us years ago, the classic thing-- very thin, very tall, long arms, some hypermobility, but not that much.

    We saw him with a CFS-- did extremely well with valganciclovir anti-viral and an anti-inflammatory hydroxychloroquine, Plaquenil, and went back to normal.

    Then he comes back for a second bout of illness.

    And this time we cannot improve him at all.

    And one of the providers thought about this, a spinal fluid leak.

    He was seen by Dr. Ian Carroll here at Stanford-- detected the leak, patched it, and he went back to normal.

    And so, the initial phase one day will be seen as a fascinating [INAUDIBLE] to work it, because of the challenges that it brings you.

    And this is an example of when the leak gets fixed, the patient basically goes back to normal anatomy, and in this case, function.

    What we do now-- when we studied early, we knew very little.

    But now we have a more comprehensive approach.

    We have a non-pharmacological component, nutrition supplements, management of the post-exertional malaise is key.

    And then we have a pharmacological approach that includes long-term-- and now long-term is five years for us-- anti-virals, anti-inflammatory drugs, immunomodulatory agents, and others.

    Heavy attention to their diet-- we are studying a study that has never been done-- even as a study that has begged to be done-- about what foods make worse or better patients.

    And patients will tell you that it's not always obvious.

    The anti-viral treatment-- there was this study that was published in the New England Journal of Medicine at the end of the '80s that completely abrogated the possibility of anti-virals.

    It was a study with 27 patients, and they gave antivirals for a total of 37 days.

    And obviously, they found that there was no difference in treatment.

    And based on that study, the whole thing was abandoned completely.

    I told you how we started with this at Stanford, and after that very first patient in February 2004 we decided to do a study on elevated titers for EBV and HHV-6.

    We were just fortunate.

    I cannot claim that I predicted it.

    I had done certain things in that way of thinking, and predicting, and modeling, and this one was a good accident.

    And in a group of patients, we do have a group of patients that no matter how long they had been sick, 20 years, 50 years, this is the extent of their illness before the drug.

    They go up, and significantly improve, and they go back to normal.

    It doesn't happen in everybody, but there is a growing number of patients that come with that history.

    Is duration of treatment important? Yes.

    So we thought that six months was long enough, and now we know that needs at least five years of sustained anti-viral for that issue of the low NK cells.

    This lead us to do-- the holy grail of clinical trial is a randomized, double-blind, placebo-controlled trial.

    So where you distribute the patient into two groups, and one will get the drug, the other one will get placebo-- a sugar pill.

    They both look identical, so patients don't know what they're taking.

    And the providers don't know what they're taking.

    And despite that it was a small number of patients, we got a statistically significant, in certain clinical markers.

    For example fatigue severity score, the lower the better the treatment group is statistically [INAUDIBLE] from the placebo group.

    Their cognitive function-- patients will tell us, my cognitive ability is x or y on each visit, and on the drug, double-blind fashion, the patients on the drug clearly told us that their cognitive function improved statistically significant, when the placebo group did not.

    We never forget the several patients who will say, I don't care on what pill I am, I am getting better.

    I'm just staying with you to help you.

    And when we broke the code, they were on the drug.

    So clearly, there is something on that drug that really helps the patients.

    And then, we show that though that drug also changes cytokines-- so it's a immunomodulator-- and another, Dr. Cory Weiss here at Stanford, has shown that also decreases microglial inflammation.

    So it's possible that it's doing it through that.

    And then, remember that I showed you that patient with zoster? We have another sub-group.

    They tend to be women in their 50s, that tend to have the herpes too in this area.

    And we see that often and often with these unbelievably horrible CFS symptoms.

    And for these patients when we suppress the virus for five years, almost always they go back to normal.

    And please know that they have been sick for 10, 20, and they have tried numerous things, and they have not worked.

    So possible candidates for anti-viral therapy-- patients with ME/CFS who are PCR positive for HHV-6, who actually have oral herpes, genital herpes-- clinically active-- shingles-- remember that shingles can be without rash.

    And that's the diagnosis of a really good internist, where they have the classical pain, never the rash, and then you can say that's herpes, and they have the CFS.

    High titers for those viruses, or those who have ongoing fluctuating viral syndrome.

    So we pay attention to these subgroups to make them candidates for anti-viral therapy.

    And these are the options for drugs that we have.

    We tend to stay away from an IV.

    We mostly use PO.

    And we are now using infusion of CMV-specific T-cells, or vitally specifically infusion of T-cells.

    We don't feel comfortable with that.

    We are not there yet.

    We hope to be there.

    The one part that we are really excited is about drugs for inflammation given that cytokine data.

    And we are slowly gathering a group of patients who remarkably get better with these drugs or combination of them.

    Based on their cytokine data, there is no way that one drug will do it.

    Or it will have to be a drug that does lots of them.

    And there is one candidate out there that could do it.

    And we're trying to get, hopefully, a sponsor to use that drug that inhibits lots of those cytokines that you saw there.

    So we are excited about that.

    Finally, the model that we're trying to create is every infectious agent that you see here has been documented to lead into CFS when the infection is severe.

    And you can see here the shingles virus.

    There is this initial protective immune response that lead patients to go back to normal lives, but there is something here that is abnormal in the CFS patients that lead to immunopathology, and perpetration, and fluctuation of their symptoms.

    And what we need to know-- what we are trying to do is, what goes wrong from protective to pathology is an unknown pathogen. It's a reactivation of those herpes viruses, or a process that has nothing to do with infection but clearly self-perpetuates the process.

    So I hope I was able to give you an overview of where we are in our group.

    Every time that you think about this disease, it's very hard not to think about how much we have failed these patients, the many patients who have taken their lives, the many patients who are still extremely sick.

    And I think that we need to still move.

    I always go in silence to this non-denominational church here at Stanford.

    I always read this part, "We must not desire all to begin by perfection.

    It matters little how we begin, provided that we are resolved to go on well and end well." And nothing of what I've done here today would have been possible without the generosity of our donors.

    Thank you.

    [APPLAUSE] Questions.



    I wanted to thank you for your presentation and all your hard work.

    It's been amazing just following this.

    I am an ME patient myself, and I also appreciate the work of Dr. Davis, who has Generously shared his time and his research.

    And it's been a long journey in dealing with this.

    And I have wondered-- you've been giving your information-- the generous information from Stanford-- the amazing website you have, guides that doctors can use.

    You know, just across the street at [INAUDIBLE] I had a doctor there, she's fantastic, as many of the doctors are there.

    However, when I brought this information to her, even with my functional capacity tests and other tests showing that I had ME, they told me, point blank, after reviewing your information, we do not prescribe vancyclovir.

    They do not do antivirals for CFS.

    And it's very difficult for patients in general to bring this to their doctors.

    It often, like you said, takes a very long time.

    But also, we're looking at something where your patients are bringing these-- Stanford's one of the most amazing places on earth.

    And when you bring research from Stanford and your doctor doesn't honor it, yet says that these are your symptoms, and this is what you have, I'm wondering-- and I think many patients that can't be here are wondering-- what recourse or things can they do in order to receive this treatment? I got a referral to your clinic, and I love you guys.

    You're wonderful.

    But your waiting list is long, because you guys do great work, and there's a lot of other people that need help.

    So that's kind of my question.


    Thank you for your question.

    The question is about how, despite that there is some work coming from Dr. Davis's group, from our group, from other groups at Columbia, and other centers, when you take the information to the providers and tell them, look at this, it's real-- these guys at Stanford, or it could be Columbia, it could be other places, are doing things.

    And they're showing that there is something effective here.

    And at least there is a group of patients with these drugs that are getting better, try them on me.

    You'll find this sad and blank response that, no, I cannot do that for you.

    And it's an impetus to do even more.

    We are in full capacity, but we need to do even more even at full capacity.

    I know you want more things sooner, but with the CDC, they have this weird association with Medscape-- I don't understand how they got together.

    But we are going live nationwide to bring physicians who see Medscape to try to send the message that at least it's real, and there is this data somewhere in one university academic center where some patients are getting better.

    So it's worthwhile to try the drugs.

    Maybe what we have failed to do is to create simple protocols.

    The valganciclovir is a drug, for example, that is not easy to use, only because it has all these warnings.

    But those warnings are because all the literature came from the transplant cancer patients and AIDS patients.

    And in those patients they have so many other drugs and abnormalities that the drug looks terrifying to physicians.

    So I apologize.

    I am so sorry that you received that.

    But that's what we hear of other patients, and it should not be that way.

    I can tell you that once in a while you-- like that patient that I told you that the physician decided to put her on valacyclovir, not valganciclovir-- we are seeing that that's happening a little bit more.

    Or I get email sometimes-- I had this vision on the antivirals for five years.

    I stopped it and then they went down.

    I put it back and they went up.

    And then how long should I now have it-- telling me that others are following this.

    I don't think we have the cure.

    We are far from that, but we do have a group of drugs that is really working for a group of patients.

    And hearing your story not only makes me sad, but also that we need to do even more to bring this message out there.

    When I was in this conference call-- I don't remember, it was last night, or the night before last night-- on this thing about the CDC and Medscape, they told me that up-to-date-- this is a resource the physicians use in the United States to get up-to-date on what to do-- and fortunately it's still, for ME/CFS, they we're recommending greater exercise therapy and cognitive behavioral therapy.

    So that's something that we're going to try to fight.

    And it's going to be an uphill battle.

    We got the CDC to remove that from the recommendations.

    I'm very sorry.

    I'm very sorry.

    And we need to do more.



    Near the end of your talk you mentioned, I think, that you were trying a drug that would be broad spectrum in terms of dealing with the cytokine storm.

    But I don't think I listened carefully enough.

    I wonder if you mind going over that a little bit.


    So with this data, you have to be open to the data speaking to you.

    And what I did is I went to several rheumatologists.

    I would take my little thing, and say, if you-- and I didn't say it was ME/CFS-- have a disease with these cytokines going up with the severity, what would be the drug in your world of anti-inflammation efforts that would best counteract these cytokines? And they gave me always two responses, one prednisone-- steroids-- because that-- but, please, that's not the drug that we are thinking.

    And the other one is Janus kinase inhibitor, called tofacitinib.

    Tofacitinib-- let's stay with the non-commercial name.

    And so we really would love to do a clinical trial with that drug, because it's the drug that base appears to counteract.

    And there are two generations of drugs coming that do the same thing that we will also explore as a possibility.


    Could you spell that name? T like Tom, O, F life friend, A-C-I-T-I-N-I-B-- Tofacinitib.

    Thank you.


    Back in 1985 during the Lake Tahoe mystery illness, a common denominator showed up right away.

    All the clusters occurred in sick buildings.

    Has anybody been interested in looking into that connection? So the question is about the fact that there were epidemics associated with buildings, and has that been explored.

    Not that I know of.

    And we don't have the expertise or the resources to do that.

    One of the things that we're trying to do is not let our own expertise be a limitation in itself, because you tend to sway things in the way that you know best.

    And that's why we're trying to bring as many people that are not in our specialty to enhance the possibility that we find whatever this finally is without that limitation.

    So we don't have that expertise unfortunately.

    Sorry about that.


    How does one find a doctor who deals with that? Oh, God.

    So the question is how to find the physician who deals with that.

    So in this CDC thing that we are trying to create-- and there is another effort at the national level, it's a committee that advises the Department of Health and Human Services, that we advise them.

    One of the things, there been this thing that, do we bring all the information to everybody, to all the physicians, or do you try to create a group of physicians that is specialized like the HIV doctors now.

    And studies have been done in CFS patients where the care is better if they know CFS than if they just try to learn how on the go.

    So what we do, is we go to this organization Solve ME/CFS, and they have a list of the providers that do that.

    Here in northern California, the Open Medicine Institute and us are the two that do the CFS targeted care.

    But we are way behind where we should be.

    And if someone asks us if we are in New Mexico or any place in the United States, we go to this organization that seems to be the one that tracks better those physicians.

    So that information is on the CGE, or? It's Solve ME/CFS.

    Is a website.

    Solve ME/CFS.

    So if I go on the website, I can find that? Yes.

    And the other thing is, if you don't mind, call our clinic here, which is right here in the second floor, and see if we can also help you with that information.

    And we are-- the clinic here, the Stanford Hoover clinic.



    And also, we are expanding the providers so that we can, hopefully, see you and more patients.

    We would like to see you.



    For those of us who've had the HLA markers done, do you have the marker somewhere on the website or something where we can view for those? So we are finalizing the-- so the markers are there-- manuscript, and we want to have input from others.

    I'm sure you understand that this is very sensitive.

    We are now clear that that's what it is, but before we publish it, we want to make sure that everybody is in agreement.

    And again, I would love Ron Davis's group and Ron Davis himself to help us with seeing this data, making sure that it's all squared.

    It will come out, and then-- yeah.

    Thank you.


    Have you identified and histopathological changes in the brain tissues in patients with this? [INAUDIBLE] the final, common pathway.

    And if there's glial cell hyperactivation, have you used low-dose naltrexone for patients with just CFS and not fibromyalgia? The question from Dr. Kenny, one of my favorite doctors at Stanford, is about how we found histopathological changes in the brain.

    So there was a brain from a CFS patients from Temple University where they did find, unfortunately, microglial.

    And they found things that are on the side, like a little bit of Alzheimer's, like plaques.

    So there is precedent for the brain being examined, and finding histopathological changes there in a CFS patient.

    When the spinal cord has been examined, they also find ganglionitis.

    And the ganglia is the area where the herpes zoster virus likes to go and cause inflammation.

    The other indirect thing for your key question is, , there was a study in Japan where they injected a tracer that goes to the microglia and they light up.

    And I'm happy to share with you that the third active study-- so we have three studies, the DTI, trying to validate that as a biomarker, we have neuroendocrine study for women in childbearing ages, and the third study is a neuroinflammation study to see if we can see what the Japanese group saw with a tracer that is more advanced.

    It's a better tracer that goes to the microglia to see if we see the microglial inflammation.

    And not wait to have a brain to-- you know.

    But we did create a brain biobank not expecting anyone to research to commit suicide, but just if the patient dies from another reason, then we are ready to analyze their brain and look for those histopathological changes.

    Thank you.

    Thank you Dr. Kenny.

    And would that be good news or bad news? So the question is-- [LAUGHTER] If you see histopathological changes, will that be good news or bad news? Every time that you see something, it can be reversed.

    So if we see it, then the whole thing will be just devoted to how can we reverse it.

    So I know what you meant, bad news, because that means that the brain is affected, which we know it is.

    So it would be good news.


    Dr. [INAUDIBLE].


    I just got this document about the common data elements where they're trying to make lists of things so that people doing research know what kind of patients to put in their research, and what measures to use.

    And I've also talked to people about that process.

    And I've figured out that they're refusing to put PEM in as something required to have-- to say that you have to have that for CFS.

    So I just wondered if you were involved in that, and what you think about that, and if there's any way you can help tell Beth Unger and the people at NIH and CDC that that's kind of nuts.

    Dr [INAUDIBLE] question-- it will not be the first thing that is nuts.

    But Dr. [INAUDIBLE] question is about, there is this effort from the CDC and the NIH called the Common Data Elements project.

    The goal with that is to arrive to a common language that all researchers will eventually use, and the minimum information that you need to have in your research so that the studies can be compared.

    And that's, in principle, a really good effort.

    Dr. [INAUDIBLE] says that it appears that there is some resistance to include PEM in this common data that everybody should have, which would be totally unacceptable.

    I wasn't aware of that.

    I got straight first-hand from people who have talked to them, refusing to do that.

    So I just wondered-- It would be-- If there was some way we could help, or you can help, or we could together help, tell them that that's nuts? Right.


    No, I talk to Dr. Unger all the time.

    We just were together at a meeting not that long ago.

    So I'll find out what happened, because PEM is one of the three diagnostic criteria from the IOM.

    You know, it's hard for me to see if the patient the patient has CFS if they don't have PEM-- that important It is.

    And I think that PEM will be the single most important factor in clinical trials being successful.

    If you don't pay attention to PEM, you could have a drug that is really good appear like it didn't work, or a drug that is not helpful doing the opposite.

    More likely it would be a good drug appearing that it doesn't work if you don't pay attention to PEM.

    So clearly you have given me an assignment tonight.

    I'm glad I got it recorded, what you said.

    [LAUGHTER] I have a question on behalf of a friend who has suffered from chronic fatigue.

    And she'd like to know-- she's had chronic fatigue for 35 years and has been recently given anitvirals-- what are the chances of this for benefiting? And is there something else he can do besides drugs? The question is that-- the person asking the question has a friend who had chronic fatigue syndrome for 35 years, she has recently been started on anitvirals, what would be the chance that she could get a significant response from there? And what would be the other drugs? One thing that we have found-- and we were not that good at the beginning-- is that it needs a comprehensive approach.

    And one of the big known pharmacological ones is this PEM issue.

    It's really critical.

    We just finished a study looking at PEM, and I wish I could have had more time to show you.

    But PEM is way more complex than we thought.

    There are patients who get PEM an hour later, and others will have it hours, the others will be 24 hours.

    There are patients who get PEM a week later.

    And so you could imagine-- and when you have, once again, in a few hours, how do you study that? And then if you study the PEM, the substances, you have to pay attention to that.

    We have not seen a single patient going back to normal with the drugs that we have given them that we have those stories if PEM hasn't been there-- it has not been conquered.

    It has not been taken care of.

    Family support is huge.

    And this is really a test for compassion, us humans.

    And then the diet can be big for some patients.

    And there are patients who will tell you they went gluten-free and clearly that helped them a lot.

    And so the key thing for the antivirals is that the benefit could be so imperceptible that patients may think they are not helping them, but it's only four or five years later that you can see that there was a difference.

    And these anti-inflammatory drugs that can be different for different patients.

    I'm sorry I cannot give you more specifics.

    Thank you.

    You're welcome.


    I was referred to your clinic early last year and I was told that I was on the waiting list and that I would be advanced to being a patient by the end of 2017.

    But I haven't heard from the clinic, and I wonder if you have any idea what current waiting time is.


    So this is a question about the waiting time in the clinic.

    And I don't have the specific information about what it is now, but I can tell you that we have our second physician Dr. Hector Bonilla with us, and we have a PA that, unfortunately, we lost, but we're going to replace.

    And Stanford is giving us support for more providers.

    I feel really bad and sorry when I hear the stories that you cannot get in, that you cannot get in.

    We need more people to come and join forces with us.



    Thank you.

    You're welcome.

    Sorry about that.

    Dr. Montoya, it is 8:15.

    Yep Thank you.

    Thank you so much--
    Last edited: Mar 4, 2018
    nandixon, Mariesak, flitza and 10 others like this.
  3. pattismith

    pattismith Senior Member

    Thank you for the big work!
    Wonkmonk likes this.
  4. Wonkmonk

    Wonkmonk Senior Member

    I find it interesting that natural killer cell functioning actually does return to normal after very long term treatment. This suggests that in this subset of patients, the virus has corrupted the immune system and when you fight the virus long-term, the immune system can recover on its own. Dr Lerners results suggested the same thing, but I don't think he had evidence in terms of natural killer cell function.
    pibee and Hip like this.
  5. JES

    JES Senior Member

    If it really takes five years to properly improve it's mostly bad news, because that makes it almost impossible to perform controlled trials. Already two years is a very long time for a controlled drug trial. There is reluctance for performing very long trials as they increase the risk of drop outs and securing financing becomes more difficult. Also I bet almost nobody would agree to take placebo capsules for five years. For example most antidepressants that are used on chronic basis have only been trialed for up to six months.
    Webdog, jpcv and pattismith like this.
  6. Hip

    Hip Senior Member

    That's true, though one workaround is the approach used by Dr Martin Lerner in his blinded placebo-controlled study on Valtrex for EBV ME/CFS: Dr Lerner ran the placebo-controlled trial for the first six months, and noted a significant improvement in the Valtrex treated patients over the placebo group.

    Then after 6 months, he terminated the placebo group, but carried on with the Valtrex treated group, for a total of 3 years.

    If you look at Table V in that study, you see there was already significant improvement of the Valtrex treated group over the placebo group at 6 months, as measured by the Energy Index Point Score. And then the study showed that the Valtrex treated group continued to progressively improve up, to the 3 year point.
    BadBadBear, Binkie4 and jpcv like this.
  7. Timaca

    Timaca Senior Member

    Thanks for sharing a link to the talk. I enjoyed watching it. My NK cell function and number are both quite low. I have been on antivirals (and at times antibiotics) for over 5 years. I wonder what my numbers were before treatment, if treatment is supposed to help improve things! :eek:
  8. Hip

    Hip Senior Member

    What I think needs to be done in the case of herpesvirus-associated ME/CFS is to find the location of these herpesvirus infections in the body. The high titers to herpesviruses that you often find in ME/CFS patients — and the fact that ME/CFS patients often respond to herpesvirus antivirals — suggest that there is an ongoing infection somewhere in the body.

    But we know that infection is not in the blood, as herpesvirus PCR blood tests often come out negative in ME/CFS.

    So where is the herpesvirus infection in ME/CFS? Which tissues or organs is it in? Finding this out should be the subject of new research.

    If you look at enterovirus-associated ME/CFS, in some ways the research is more advanced in this subset, as there have been numerous studies finding chronic enterovirus infections in the gut, muscles and brain tissues of ME/CFS patients. So in this subset, the high enterovirus antibody titers would seem to correlate to these ongoing enterovirus infections that we have proven exists in the tissues.

    So why aren't herpesvirus ME/CFS researchers performing these sort of tissue biopsies on patients, to try to find the location of these chronic herpesvirus infections?
    Mariesak, flitza, anni66 and 2 others like this.
  9. junkcrap50

    junkcrap50 Senior Member

    I agree. Many ME/CFS doctors also don't do spinal taps to test the CSF for viruses and antibodies. And that's easier than biopsies. You would think that infectious disease doctors would have some experience doing those. The only ME/CFS doctor I know who orders CSF testing is Dr. Peterson

    Shouldn't previous studies where they conducted autopsies on ME/CFS patients have given us the answer on this?
    anni66 and Learner1 like this.
  10. Hip

    Hip Senior Member

    Yes, Dr Peterson uses CSF tests in clinical practice, but to my knowledge he has not published any of his findings on this area.

    Though he says in this slide presentation that he finds 16% of ME/CFS patients are positive for herpesvirus infections in the CSF, which is not a very high percentage.

    But if these brain or spinal infections are abortive of latent infections, they will not create viral particles, so PCR tests of CSF may be negative, in spite of the presence of an infection. That's why it's probably better to perform brain biopsies, when you can test the actual brain tissues for the presence of infection.

    When these brain autopsies and muscle biopsy studies were performed in the 1990s in the UK, the focus was mainly on enterovirus, because I don't think the herpesvirus theory of ME/CFS was well established at that point.
    Last edited: Mar 5, 2018
  11. Wonkmonk

    Wonkmonk Senior Member

    Is there another viral infection that is known to affect tissues/organs so dramatically, but does not show up in the blood as IgM or in PCR at all? I'd say, that's the main missing link in the infection theory. If there is a widespread infection, and it must be widespread, it should also be in the blood.

    I could only think of the convalescence phase of infectious mononucleosis, where viremia has stopped, but fatigue and other symptoms persist for some time. As far as I know it is unknown why it persists, but one reason could be continuous EBV activity. Post-herpetic pain after Herpes Zoster could be another case, but here I think permanent damage to nerves is suspected and not continuing viral activity in organs/tissues.

    Dr Lerner did heart biopsies to check for fat deposits in the heart, which is a sign of organ damage he suspects is caused by herpes virus.

    But I don't recall him testing the biopsies for herpes virus, which is strange. He stopped these biosies after some patients had episodes of severe bleeding.
  12. dreampop

    dreampop Senior Member

    I think @Jesse2233 was interested in Tofacitinib at one point. I would be very interested to see trials from that. But, again, no obvious inflammation that warrants it.
  13. pattismith

    pattismith Senior Member


    the scientific papers I read are talking about a latency of alpha HV (HSV1, HSV2, Varicella Zoster) in sensory ganglia.

    "sensory ganglia are oval swellings located on the dorsal roots of spinal nerves and on the roots of certain cranial nerves."

    ex: vagus nerve and trigeminal nerve

    The quick reading I've had for other HHV were contradictory so you may dig more into it to find updates:

    "beta HV (cytomegalovirus) can establish latent infection in secretory glands, cells of the reticuloendothelial system, and the kidneys."

    gamma HV (EBV, HHV6, HHV7, Kaposi):

    "Latent virus has been demonstrated in lymphoid tissue.
    Epstein-Barr virus can maintain latency within B lymphocytes and salivary glands.
    (cytomegalovirus), human herpesvirus 6 and 7, Kaposi's sarcoma herpesvirus and B virus have unknown sites of latency."


    Update on Cytomegalovirus:

    "The prevailing view of HCMV latency was that the virus was essentially quiescent in myeloid progenitor cells ... latent infection is far more active than first thought..distinct sites of cellular latency could exist in the human host,..."

    "Latent carriage of HCMV in CD34+ progenitor cells and their myeloid derivatives"

    Update on EBV:

    'Horwitz and colleagues showed that EBV can infect human BMVECs, where it becomes latent' (Brain microvascular endothelial cells)
    Last edited: Mar 5, 2018
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  14. heapsreal

    heapsreal iherb 10% discount code OPA989,

    australia (brisbane)
    My experience is i noticed a positive effect from AVs after 3 months and about 6 months to confirm they were indeed helping but not cured. Ive been on famvir since 2009 and had a short stint on valtrex which didnt help and tried combining it with famvir, it may have helped. Also did 18months on famvir/valcyte that was positive.

    But it has been up and down, as i have stopped avs for short periods of time to see if i could hold my improvements. Ive lasted as short as a few days upto a couple of months, which i think i did once.

    A few theories i believe with my situation is that the viruses are a very low activity when doing well to very high activity when crashing, rarely dormant. I believe the avs dont stop these viruses from being active and feasting on its host but they stop the virus replicating and over time the viral load drops as the virus naturally die off and no new viruses are made. I believe thats why it can take along time to put these viruses to sleep, as in years. And maybe never truly knock the virus out.

    I dont believe medicine can really detect an active infection unless its brand new first time infection or it is very overt and you are close to or in septic shock, that they will detect viruses in blood or cerebral spinal fluid. I think these viruses are sitting in the nervous system and occassionally small amounts of virus enter the blood stream to locate elsewhere.

    I did use arvs for awhile and they would help for short lengths of time, so stopping and restarting would bring back some improvement . My experience with arvs i believe were through its ant inflammatory action which would decrease with continued use until i took a break from them.

    Im guessing but about 2 yrs ago i stopped famvir, so 8 yrs on avs, within days had a shingles infection which reoccurred several times in varying degrees even while on avs but not as severe. Id like to try stopping avs again but very reluctant as im doing quite well.

    What viruses was i dealing with? cfs onset cmv/vzv/ebv within several months of each other, tests over 12 months later were totally negative to ebv ie no igg life long titres, strange? Several years after onset i had 1 cmv igg titre level test that showed cmv titres could be high enough to be an active infection and was unable to get further tests. Then multiple vzv/shingles episodes . It could be any combination of the above???

    Chicken or the egg if the infection came first or the immune dysfunction??
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  15. heapsreal

    heapsreal iherb 10% discount code OPA989,

    australia (brisbane)
    Herpes sine, shingles virus without a rash. Also mollarets meningitis which is from viral reactivation of hvs1 or 2 and varicella. So its very possible. Mollarets looks almost identical to cfsme.

    I believe Sophia Mirza who's cause of death is ME, one of her autopies showed lessions on her spinal cord which showed inflammation caused by dorsal root ganglionitis, similar to varicella zoster virus or similar virus.

    I think its worth mentioning??
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  16. Wonkmonk

    Wonkmonk Senior Member

    @pattismith I found this online, but I have no clue if it makes scientific sense:

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  17. Wonkmonk

    Wonkmonk Senior Member

    Did you ever consider adding anti-inflammatory drugs, e.g. hydroxychloroquine, as Dr Montoya mentions above?
  18. Hip

    Hip Senior Member

    Yes, in the case of enterovirus, it's called a non-cytolytic infection. A normal enterovirus can convert into a non-cytolytic enterovirus under certain conditions in the body.

    These non-cytolytic infections exist as chronic intracellular infections, which can be located in the tissues, but do not produce any new viral particles, so you don't see much virus in the blood, and hence why a blood PCR will often be negative in ME/CFS. But if you instead perform PCR on some of the tissues infected with this non-cytolytic form of the enterovirus, like the muscle or gut tissues, then you will get a positive result.

    All the early research on enterovirus ME/CFS used to take muscle tissue biopsies from patients, and they would find enterovirus in the muscle by PCR tests. So these non-cytolytic enterovirus infections are proven to exist in the tissues of ME/CFS patients.

    I think I saw one of Dr Lerner's papers where he did test for herpesviruses in the heart tissue biopsies of three ME/CFS patients, and I believe he found all three biopsies positive for herpesvirus.

    And also in one of the enterovirus studies I saw, they also found Epstein-Barr virus in the muscles of some ME/CFS patients (but no ME/CFS patient had both EBV and enterovirus in the muscles in that study).
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  19. Hip

    Hip Senior Member

    I have also seen those ME/CFS theories of herpes infection in the nerve ganglia.

    In fact Dr William Pridgen's theory is that herpesvirus infections in the nerve ganglia are causing fibromyalgia, and possibly also causing ME/CFS. The special antiviral protocol (Famvir 250 mg twice daily + celecoxib 200 mg twice daily) he devised to target these infections. His phase II trial of his protocol for fibromyalgia had good results.
  20. pattismith

    pattismith Senior Member

    I think this will be my next target, once I will get rid of my intracellular bacterial infections...thank you to remind us the protocol :thumbsup:

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