A discussion of anti-retroviral drugs in the treatment of ME

There's an interesting thread on Phoenix Rising about the use of anti-retroviral (ARV) drugs in the treatment of ME.  Many people, including my doctor, Dr. C, believe that ME is caused by retroviruses. (Dr. C specifically focuses on enteroviruses, which are a type of retrovirus).  The entire thread is worth reading, but if you are short on time, here are a few highlights:

[First, I must give the caveat that the original post in the thread consisted largely of a Google translation of a blog post by a German doctor.  The translation is not perfect and it is not always possible to discern the meaning, but this is my best attempt.]

• A German doctor/ME specialist, Katerina Voss, who has successfully treated patients, including her own daughter, using a the ARV drug tenofovir (brand names: Viread and Truvada) (a Hepatitis B and HIV drug) .
• Dr. John Chia has succesfully treated some patients with the ARV drug lamivudine (brand name Epivir) (developed for Hepatitis B and HIV). 
• Voss states that a potential side effect of ARV treatment is impaired mitochondrial function, which is already a problem for ME patients in the first place.  To combat this, she recommends supplementing with "N-acetylcysteine (NAC, caution in histamine intolerance !), Glutathione or niacinamide (Vitamin B3 flush-free)."
• One poster states he/she anecdotally knows of about 30 patients who have improved using ARV treatments. 
•  Other posters report success with herbal ARV scutellaria baicalensis, also known as Baikal skullcap or Chinese skullcap.  There is no information on dosing.
• ARVs might lead to improvement not because of their anti-retroviral properties, but because they can also be immune modulators. This is always a possibility.

The full thread can be found here... https://forums.phoenixrising.me/index.php?threads/blogger-katarina-voss-writes-a-comprehensive-article-on-treating-icc-me-with-antiretrovirals.60633/

In 2012-2013, I wrote about my experience trying Epivir under Dr. C's care.  Here are excerpts from the two pertinent posts:

Before trying Epivir:

Epivir

Epivir is an antiviral that was originally used to treat HIV patients.  HIV patients often initially experienced significant improvement with Epivir, but the virus would then adapt to the Epivir after a year and the drug would lose it's effectiveness.  For this reason, it was later used in combination with other antivirals to have a more long-lasting benefit.  Dr. C believes it can have a more long-lasting benefit for PWME's as well, even without combining it with another drug.

Dr. C states that Epivir is a fairly safe and non-toxic drug, with few significant side effects being reported.  The side effect known to Dr. C, lactic acidosis, is theoretical - Dr. C has never seen a patient who actually experienced it.  

Dr. C's studies have shown that Epivir can be effective when combined with Equilibrant for some patients, and when combined with Inosine for others.  It works in about 30% of the patients for whom he has prescribed it.  When it does it work, it seems to work quite well.  

Dr. C related several anecdotes in which patients had very good success with Epivir, including a story of one patient who was apparently brought back to nearly normal functioning by a combination of Epivir and another unspecified antiviral (Valcyte?)  Dr. C cautioned however, that Epivir is not something that normally cures patients...in other words, if a patient improves and then stops taking the drug, the virus will come back just as strong as before.

And after attempted treatment with Epivir:

Epivir

Next we discussed how I tried Epivir but was forced to quit after only 3 days due to a major flare in my shortness of breath, which landed me in the Emergency Room.  Dr. C stated that he and his team have recently discovered that some antivirals actually increase the replication of certain viruses while suppressing others. Since I haven't had a stomach biopsy and we don't know what specific enterovirus I (may) have, we're doing guesswork at this point. He said that the shortness of breath could also have been a die-off reaction, or it could have been the stimulation of viruses in my lungs.  He said it's not worth testing either theory and I agreed. 

To illustrate the point about antiviral medications having different effects depending on the virus, Dr. C mentioned that patients for whom echovirus 6 and/or 7 is a major contributing factor to their ME/CFS don't respond to Epivir.  Epivir is simply ineffective against echovirus 6 and 7, but very effective against other viruses. 

Beware of Supplements that May Cause Kidney Inflammation or Damages

Since I first developed ME in 2011, one of my on-again-off-again symptoms has been an aching in the area of the kidneys.  Two separate nephrologists (kidney doctors) tested my kidney function and told me it was normal and that I did not have any kidney stones, and yet these aches would persist.  In recent years, the pain has been mostly absent, but would come back 4 or 5 times per year.  

In the past three weeks, the pain has been back again.  It usually comes with strong, persistent thirst. I wondered if there are any supplements that could help reduce this inflammation.  In the process of searching for supplements that would help, I came across this list of 17 drugs and supplements that, according to the American Society of Nephrology, have been associated with kidney inflammation. One of them, to my surprise, was L-Lysine, which I have been taking at a "maintenance dose" ever since my outbreak of the shingles.

It's probably important for anyone who takes supplements to check this list and make sure they are not potentially damaging their kidneys.  

Antivirals May Treat M.E., But For Different Reasons Than We Thought

If you haven't already, check out this article from the Open Medicine Foundation (OMF).  It starts with a general overview of theories of the role of viruses in ME and various approaches to treating the viral component of ME.  But it's conclusion is perhaps the most interesting.  The article concludes that using antiviral treatments for ME may help improve symptoms in patients, but not because antivirals actually decrease viral titers, but because they improve metabolic function.  Again, this seems unproven and possibly speculative at this point, but it does seem to reconcile the puzzling results of some studies on the use of antivirals in ME treatment.

http://www.openmedicinefoundation.org/2016/09/09/viruses-and-cfs-statement-by-ron-davis-and-bob-naviaux/

Have You Seen This Table of Recent ME Research Findings?

I don't know what saintly person created this table of recent ME research findings, but I wish I could thank him or her.  I'm always looking for ways to simplify and makes sense of the vast amount of information that comes at us in the ME community.  Recently, I have felt less motivated to keep up with all of the research findings because it all starts to seem like disconnected noise after a while; none of it leading to any real-world solutions for us.  Charts like this are helpful to see the "big picture."

https://drive.google.com/file/d/0B_Dn3IXWlI9fTGdpSjkzcmtWRUU/view?pref=2&pli=1

Article: biomarker for ME might be found in the gut biome

This article from Cornell Chronicle summarizes recent findings published in the journal, Microbiome, reporting that researchers could predict whether a person has ME based on the diversity of their microbiome, using stool samples.

"The researchers sequenced regions of microbial DNA from the stool samples to identify different types of bacteria. Overall, the diversity of types of bacteria was greatly reduced and there were fewer bacterial species known to be anti-inflammatory in ME/CFS patients compared with healthy people, an observation also seen in people with Crohn’s disease and ulcerative colitis. 

At the same time, the researchers discovered specific markers of inflammation in the blood, likely due to a leaky gut from intestinal problems that allow bacteria to enter the blood, Giloteaux said. Bacteria in the blood will trigger an immune response, which could worsen symptoms."

These might not be the most revolutionary findings, especially regarding the lack of diversity in gut bacteria (first quoted paragraph above), but I had never heard that it was, specifically, bacteria, that leaks into the bloodstream in leaky gut syndrome (second quoted paragraph).  The leaked substance has usually been described more generally as "particles" or "toxins" leaking into the bloodstream, not necessarily bacteria.  Could this be a significant finding?

Still, the articles doesn't address some obvious questions.  What is the connection between the lack of diversity in the gut biome and the leaky gut condition which allows some of those non-diverse bacteria to enter the bloodstream?  And what are the "specific markers of inflammation in the blood" the article references? Unfortunately, we would have to access the original publication in Microbiome to find out.  

Dr. C on the hunt again

Yesterday I had my first appointment with Dr. C in about a year.  Dr. C is an ME/CFS specialist who is fairly well known in some circles.  The main reason I visited Dr. C this time was to solicit his opinion on my recent, questionable Lyme disease diagnosis.  He did not disappoint.

Research Update

CDC Tests Samples - No Luck

First, as usual, Dr. C brought me up to date on the most recent developments in his corner of the ME/CFS research world.  Dr. C adamantly and passionately believes that ME/CFS is caused by infection by enteroviruses.  For years, Dr. C has been trying to convince the U.S. Centers for Disease Control (CDC) to search for enteroviruses in his library of stomach biopsy samples from 2007.   They recently agreed and Dr. C sent some of his samples to the CDC.  Unfortunately, the CDC was unable to detect the presence of enteroviruses in the samples.  If I understood him correctly, Dr. C seemed to think that the CDC's failure to find evidence of enteroviruses in these samples was due to their age.  He asked them to search again using a different, more sensitive technique and they declined.

RNA Sequencing of Samples

In recent years, Dr. C has also been working with a biologist from Cornell University.  He sent the Cornell researcher a portion of his stomach biopsies, some from moderate patients and others from more severely ill patients.  Rather than look for enteroviruses, the Cornell researcher took the novel approach of sequencing the RNA in the samples.  She started with the samples from moderately ill patients and apparently the patterns she found were unusual.  (The question of what exactly was unusual about the samples was apparently too complicated to explain to me, a lay person, in the context of a doctor's appointment.  I of course understand.) Dr. C is anxiously awaiting the results of the sequencing for the samples from severely ill patients.  He seemed to think this could be a breakthrough.

Vagus Nerve Research  

Dr. C also mentioned some fascinating research from a Danish group of scientists involving the Vagus nerve.  In decades past, doctors sometimes resorted to severing the Vagus nerve of patients who presented with persistent and otherwise untreatable stomach ulcers.  (Thankfully, we no longer treat ulcers this way.)  But as a result, there is a significant population with severed Vagus nerves, which offers an opportunity to study the role of the Vagus nerve in overall health.

Some patients with Parkinson's acquire the disease in sudden onset fashion, after suffering severe flu-like symptoms.  (Sound familiar?)  There is a much lower incidence of Parkinson's disease in people whose Vagus nerves have been cut.  The Danish team believes this is because Parkinson's is sometimes caused by either Enterovirus 71 or Coxsackie B - 4, which enters the body through the stomach and travels from the stomach to the brain via the Vagus nerve, bypassing the blood-brain barrier. The Danish team will publish their evidence soon.

For years, Dr. C has looked for evidence that enteroviruses migrate from the stomach to the brain via the blood.  He never quite found the evidence he was looking for.  He believes the Vagus nerve possibly makes more sense as the vehicle by which the virus travels from the stomach to the brain.

Drugs for ME/CFS

After discussing a new potential drug that could help ME/CFS patients, the details of which Dr. C said were confidential and "not to be shared,"  Dr. C said that it is just a matter of time before we have a drug designed specifically for ME/CFS.  "There will be a drug" he said.  He offered no specifics on his prediction of timing for this drug, which I conclude could mean it's anywhere from 5 to 55 years away.  The good doctor estimates that there are about 4 Million ME/CFS patients in the United States alone.  He said the numbers are often underreported because there are many patients in the "mild" or "functional" category who often aren't counted in the ME/CFS statistic, but who would be candidates for any drug.  His point was that 4 Million patients gives the drug companies plenty of financial incentive to develop an ME/CFS drug.  But I wondered, do the drug companies know there are 4 Million wallets out there begging to be plundered?  

Shortness of Breath

I mentioned to Dr. C that I'd taken a bit of a downturn since the second quarter of 2015, in no small part because shortness of breath has decided to pay me an indefinite visit. He asked if I'd seen any specialists and I mentioned my consultation with a pulmonologist, including the CT scan and echocardiogram.  Dr. C said that none of those imaging techniques will reveal the cause of shortness of breath in ME/CFS patients because they only examine large airways.  The problem in the lungs of ME/CFS patients is inflammation in the microscopic airways.  The only way to detect this type of inflammation is through biopsy.

Dr. C went on to describe one of his ME/CFS patients who was so severely stricken by lung inflammation that she was often hospitalized for three weeks out of every month, and required near constant oxygen supplementation through a tracheostomy (a surgically created hole in the neck).  One of her treating physicians had placed her on high dose prednisone, which lead to a worsening of her condition and nearly killed her.

Dr. C was part of the team that was called into the hospital to decide how to handle this patient, who was a mystery to all but Dr. C.  Because the patient's blood tests were mostly normal, some of the doctors suggested that she was simply holding her breath!  In other words, she was a faker.  Dr. C expressed some anger as he described this, even 'dropping an F bomb,' which I found both endearing and amusing.  I like this guy.

Lyme Disease?

I told Dr. C that I had recently received a positive Western Blot test for Lyme and that I was skeptical of the results.  He asked if the results were from [_______] lab.  I said yes.  He smirked and shook his head.  I said, "So you think it's bullshit?"  (Now that Dr. C had cursed with me, I felt I could express myself freely.)  He said "Yes, it's bullshit."

Dr. C said that the Western Blot test is notoriously inaccurate.  He said that he, himself, sometimes performs the Western Blot test in his lab, and that the results vary even when performed twice on the same sample.  He said there are two labs in the country where "everyone's" samples comes back positive for Lyme.  [_______] lab is one of them.  

He also explained that its doesn't make sense that my results would be positive for IgM and negative for IgG (as I too had questioned.)  Some LLMD's will claim it's because a Lyme patient's body has a deficient immune system, caused by the Lyme itself, but Dr. C said a compromised immune system still wouldn't result in +IgM/-IgG.  

Having had the vagaries of Western Blot testing explained to me by someone who actually performs the test was convincing.  When I first received the test results, I wrote that I felt there was about a 51% likelihood I actually had Lyme.  Now I would say my level of certainty (or uncertainty) has fallen to about 10%.  It is possible, however, that just as LLMD's are often accused of "seeing Lyme in everything," perhaps Dr. C sees enteroviruses in everything, to the prejudice of everything else.  

I have to think about my treatment plan a little more, but for now I'm thinking I will simply continue with Byron White Formula's A-L Complex, and do nothing further about the possibility of Lyme.  In all other respects, I will continue as if I have ME/CFS only and continue with all my other ME/CFS supplements (many of which are used by Lyme patients too).  A-L Complex is, after all, sold as a general immune booster, so it should be helpful regardless of which disease I have.  With that plan, either way, Lyme or ME/CFS, I have at least some of my bases covered.  

Inosine

Finally, we discussed that I am going to try over-the-counter inosine again as an immune modulator.  I tried it once before but stopped because I thought it might be responsible for a bout of costochondritis (a type of chest pain) which arose soon after I started inosine.  Dr. C thought it was unlikely the inosine cause the chest pain, but possible. 

The backlash against gluten-free diets: why it's wrong

We've all seen it.  And it was predictable.  There's a heavy backlash against gluten-free dieters and it's only getting stronger.  The negativity toward gluten-free dieters can get downright nasty--they're portrayed as silly trend-followers who don't really understand nutritional science.  The backlash shows up on an almost daily basis in the form of punchlines on nighttime talk shows or snide comments from your friends and co-workers.

Here's why the backlash is just plain wrong...

First, let me establish that I don't have a dog in this fight.  I don't follow a gluten free diet per se.  I do eat a low-carb, Paleo-ish diet, which happens to mean I consume little gluten as compared to, say, someone on the standard american diet (SAD).  But if I want to eat a particular food that otherwise fits my diet and by chance contains gluten, I won't hesitate.

Second, let me say a few words about why there's a backlash.  It's two simple reasons:  There is a small minority of people who simply cannot shut up about their gluten-free diets.  They utterly fail to comprehend that there are few things less interesting than hearing about someone's specialized diet. These people invited the backlash and they unfortunately raise ire against everyone else who modestly adheres to the diet because it makes a difference in their day-to-day well-being.

My advice to these gluten-free megaphones: become as low-key about your gluten-freeness as you possibly can. If you're looking for something suitable on a restaurant menu, figure out a way to ask if it's gluten free without making it sound like you'll die if a speck of gluten crosses your lips - and preferably without even using the word "gluten."  I assure you that's quite possible.

The other reason is that most people (especially we Americans) just aren't comfortable not having a strong opinion about a topic that has entered the public consciousness. We're an opinionated people for better for worse--mostly worse.  We go to the grocery store and it seems like half the product labels scream "Gluten-Free" and we want to have something to say or tweet or status-update about that, damnit.  So we feel like we're somehow obligated to choose one side of the issue of the other; either we're a gluten-free champion or a bitter cynic.  Just once I'd like to meet someone who says, "You know, I don't really have an opinion on gluten.  I haven't read enough about it to form a knowledgeable point of view."

Nintey-five percent of the time, when a gluten cynic shares their viewpoint, it goes like this:  "Gluten is only a problem for people with Celiac's disease.  If you don't have Celiac's, gluten is not an issue."

Ah, if only nutritional science was so simple.  That's like saying, "If you don't have diabetes, you can eat as much sugar as you want without any health repercussions."

Here's the real deal.  Yes, Celiac's is a serious auto-immune disease and being gluten-free is imperative for people with that disease.  But for the rest of us, there's still a large and growing body of research that suggests that gluten is pro-inflammatory.  And inflammation has been implicated as a root cause of a range of diseases, from heart disease to Alzheimer's; from autism to migraines, and many more.

Even if you don't have any of those diseases, you simply won't feel as strong and as healthy as you otherwise would if you have excess inflammation.  The inflammation might be sub-clinical (you're hardly aware of it) but it could be keeping you from feeling more energetic, clear-headed, and healthy.

This past Summer, the results of a study were published that purported to cast doubt on whether non-Celiac's gluten sensitivity was 'a real thing.'  This of course became translated into attention-grabbing headlines proclaiming the whole gluten-free craze to be some sort of hoax.  Witness the utter glee behind these "neener-neener" headlines, which totally misrepresent the study they reference:  Google results for "gluten proven false."

First, the actual "study" that was referenced in these headlines, from Monash University in Australia, followed only 37 people, which is about as significant as as a wisp of dust.  The study tracked the subjects for...one entire week!  The patience of those intrepid scientists is astonishing, isn't it?

But more importantly, even if you were to take the results of that one small study seriously, it only purports to cast doubt on a condition called "non-Celiac's gluten sensitivity."  Again, let's go back to the sugar analogy.  I don't think anybody doubts that refined sugars, in the large amounts consumed in the SAD, are bad for one's health.  It's not just about the immediate affects. Over a lifetime, consuming high amounts of sugar leads to obesity and diabetes, among other things.  This process plays out over a very long time, and does't require any kind of sugar "sensitivity" condition.

Studies suggest that the pro-inflammatory affect of gluten may operate in the same way.  Having looked at the studies showing the pro-inflammatory affects of gluten, it's really hard to discount them. (See, e.g. 1, 2, 3, 4, 5, )  Nobody has refuted any of these findings.  Certainly it doesn't take a degree in nutritional science to understand the difference between the myriad studies that observed the actual chemical process leading to inflammation from gluten, as compared to single study that followed a group of self-selecting gluten sensitive subject for a mere 7 days.

But of course we know which study made the headlines.

I'm not saying that anyone has proven with 100% certainty that gluten is categorically bad, in any amount, for 100% of the population.  Like most controversies regarding nutrition, A) there will never be enough evidence to remove all doubt, and B) the actual answer is probably highly nuanced, meaning it's possible that gluten has both benefits and detriments, and that the "right" amount depends on a number of variables, including difference in each individual's biochemistry. Again, think of sugar.

But if you're one of those bitter gluten cynics, you might want to ask yourself how sure you are that you're correct.  Even if you're not completely convinced by the gluten/inflammation connection, you'd have to admit that there's credible evidence in favor of it--a lot of it.  If you can refute the five studies I've linked above (a tiny sample), let's hear what you got.  Until then, do you really want to be rolling your eyes and making fun of people on an issue that is, at the very least, unresolved?  It's a legitimate debate and you ignore that at the risk of looking like a fool...

With the weight of the evidence pointing toward at least some real and significant problems associated with gluten consumption, it is likely you will be on the wrong side of history when all is said and done.  Might as well save yourself the backtracking now and quietly let each person explore for themselves whether reducing gluten intake is beneficial to them.  Let's all check back in 10 to 15 years and see what science says then.

I predict that, in the short term, the gluten backlash will get stronger until most gluten-free dieters are basically forced into the closet.  But the movement will quietly stick around until it gains more acceptance and, eventually, becomes more or less a permanent part of the conversation, just like....

sugar.

The Possible Connection Between Prostatitis and ME/CFS

The prostatitis that I wrote about in November and December seems to be back.  This is not a surprise. Prostatitis is inflammation in the prostate that can sometimes be caused by a bacterial infection, but is more often caused by general inflammation of the prostate.

My November-December episode of prostatitis wasn't the first and the urologist told me it probably wouldn't be the last.  He said that after one contracts prostatitis, it tends to slowly become a chronic condition.  It may be a lifelong companion.

The question in my mind has been: is this related to ME/CFS, or just another sign of getting older?  I believe it is probably related for several reasons.  First, I never had chronic prostatitis before ME/CFS.  Before, I had one bad episode of a urinary tract infection, and would occasionally get some mild symptoms similar to what I experience now--but nothing as severe as this new pain.  

I now believe those early, mild symptoms were warning signs.  I believe they were signs that the underlying cause of my ME/CFS (a weak immune system) had been building toward a tipping point for some time before I came down with ME/CFS. (More on why I believe that in a future post) 

As I researched prostatitis, I began to see many familiar themes from the ME/CFS community.  Prostatitis is normally a chronic condition of unknown origin.  It tends to baffle doctors.  Doctors (even urologists) often become frustrated with chronic prostatitis patients because they don't know how to solve the patients' problems. (Prostatitis Foundation).  Sound familiar?  

Prostatitis is essentially a disease of inflammation.  While a small percentage of acute prostatitis cases are caused by bacterial infection, most are caused by inflammation of unknown origin. (Prostatitis Foundation).  

Here's a list of the possible causes of prostatitis, from the Prostatitis Foundation website.  I've highlighted the areas of cross-over from ME/CFS:

• Bacterial infection,
• Auto-immune response or disordered immune response,
• Neuromuscular, tension or physical injury problem
• Additional possible causes:
• a uric acid disorder,
• prostate stones,
• a urethral stricture,
• a rare tumor,
• prostate cancer,
• benign prostatic hyperplasia (BPH, non-cancerous growth of the prostate),
• a food allergy,
• a yeast infestation,
• a specific yeast problem from the Genus Candida,
• or a virus. (Prostatitis Foundation)

Just as with ME/CFS, since the medical community is of relatively little help in dealing with chronic prostatitis, many sufferers turn to self help techniques.  Self help often includes dietary supplements and the exchange of information with other patients in online forums.  

And then there's this quote from the Prostatitis Foundation website:

There's growing interest in the idea that prostatitis may be caused by immune disorders or allergies, in which case treating the inflammation is the way to go. ... There are research trials underway with the drug Elmiron, which addresses auto-immunity and mast cell responses. And antibiotics themselves have anti-inflammatory benefits. (http://prostatitis.org/methods.html)

Then there is the Candida connection.  It seems both ME/CFS and prostatitis often go hand-in-hand with Candida overgrowth, which points back to immune dysfunction.

A significant number of men with chronic prostatitis have found relief ranging from a cure to welcome diminution of symptom severity after following an anti-candida regimen. .... 

It is uncertain whether a yeast overgrowth in the gut lowers general body resistance by attacking the immune system, thereby allowing dormant bacteria in the prostate to re-activate (proven science: [Candida] toxins disarm elements of the immune system), or whether the effects on the immune system result in non-bacterial inflammation to the prostate tissue (and often the sinuses as well - another poorly perfused part of the body), or indeed whether the organism actually infects the prostate tissue directly....

Here follows a shortened list of the associated symptoms which typically accompany a CA-induced prostatitis ... painful lymph nodes ... unexplained fatigue ... always catching colds and flus ... mental confusion, fogginess ... cold hands and feet ... (http://prostatitis.org/fungus.html)

All this gives rise to the possibility in my mind that prostatitis is yet another related or "co-morbid condition" with ME/CFS.  The good news is that, before ME/CFS, I would have probably visited a couple of doctors, who would probably shrug and fail to offer much help.  At that point I would have simply accepted that this condition is just a new fact of life.  Now, I'm much more motivated and have the tools and general understanding of the inflammatory conditions in my body to actually do something about it.

Just like with ME/CFS in general, I'm going to start trying various treatments (both self-help and through doctors) until I find something that works best for me.  But I know now not to rely solely on my doctors.  I know to take responsibility for my own care and to research and understand the condition as well as I can... and most importantly, to be a partner with my doctors, not just a blind follower.  I'm optimistic that, while I may not find a cure, I'll find ways to gain at least some measure of control over the symptoms.  In the end, that's all I can ask for.


End Note: For those thinking that I may have prostate cancer, I have had a couple of digital rectal exams [DRE's] in the last couple of years, and all were unremarkable.  But, from what I've read, one must always rule out the possibility of prostate cancer when he has symptoms of prostatitis.

Did we just take a HUGE step toward a unified model of ME/CFS?

It seems as if every day there's an article discussing new research findings and treatment theories in the ME/CFS blogosphere.  In the first year or two of my illness, these articles excited me.  I read every single article and blog post about new theories and treatments.

Then, after a while, I started to realize that most often nothing becomes of these promising leads.  We never hear about them again.  In the past year, I reverted to simply skimming the headlines and surmising the gist of most articles.  I look for anything that sounds like a true breakthrough...or anything that "connects the dots" with prior research.

After this year's IACFS Conference, I felt conflicted again.  All the information I'd absorbed sounded so promising, and yet, we still had dozens of different theories, each of which only seemed to explain a portion of the disease.  There was no serious attempt yet to synthesize the various research findings into a unified model.

Here's what I wrote after the IACFS Conference:

The next big breakthrough in ME/CFS research. ... will be the first. 

As sobering as that is, we can't point to any one finding over the last 30 or 40 years that truly qualifies as a "breakthrough."  I'm referring to a breakthrough on the order of the XMRV discovery....had it turned out to be correct.   

We have nothing like that.  So when I read accounts of the IACFS conference, or the daily articles that make the rounds in our blogosphere, I have mixed feelings.  A few dozen dedicated researchers are working on their pet theories and all seemingly churning out important findings.  It all sounds positive...we are surely making "progress"!  Right?

But it raises the question: Is one of the researchers correct, and the others wrong?  I think, almost certainly not. There are too many confirmed physiological abnormalities found in ME/CFS patients that are, by now, beyond debate.  In the immune system alone, there is a constellation of problems, and that's just one part of the disease.  We know with absolute certainty we're dealing with a complex multi-system disorder. And so each of these dedicated ME/CFS researchers is probably focusing on what will turn out to be but a small piece of the puzzle. 

When a true breakthrough finally occurs, it will look like one of two things:  Ideally someone will suddenly discovery the etiological cause--the one event that sets off the long chain of subsequent physical derangements.  Then we'd have a true focus for treatment research. 

But barring such a "homerun" discovery, true breakthroughs will begin to occur when someone with a mind toward the "big picture" starts making connections between the various derangements.... and proving them.  Someone has to start linking these findings in a causal chain so that we can begin to create a comprehensive model of this impossibly complex disease. 

It appears that one of our beloved ME/CFS researchers is finally starting to do just that--to look at the big picture and develop a unified theory.  If you haven't yet read Cort Johnson's article summarizing Dr. Lucinda Bateman's recent pronouncement, you really should.  The one-sentence version is that Dr. Bateman has developed the beginnings of a unified theory, where ME/CFS starts with inflammation in the limbic part of the brain.

It's true that others have proposed general theories before about how everything fits together, but I don't believe it's been done with this level of clarity and confidence -- and by someone who is respected as a leader in ME/CFS research.

I've been a strong proponent on this blog that a unified theory will start and end in the brain--the hypothalamus specifically. (Examples 1, 2)  That of course isn't my theory, but it's the one that always made the most sense to me because it is the only one that could explain all the myriad symptoms and derangements we experience.  Bateman is now saying it's not just the hypothalamus but it's inflammation in the entire lower portion of the brain.  More importantly, she's gone beyond the stage of idle speculation and has actually coalesced the research findings of her colleagues into a well thought-out hypothesis that makes a lot of sense.

What We Need to See Next

Obviously we're still a very long way from solving this disease, but here are a few things I'd like to see happen to push us closer to that goal.

1.  Naturally, the hypothesis needs to be tested... extensively.  This will be a long and expensive process (maybe a decade or more?) but I truly believe that it will be confirmed, if not refined a little in the process.  

2.   The theory needs to be expanded to explain some of the other derangements we see in ME/CFS patients, especially in the immune system.  Dr. Bateman speaks of auto-immunity (overactive immune response).  But what about other aspects of the immune system that are under-active in ME/CFS patients (specifically Natural Killer Cells, and usually, one or more IgG subclasses)?  Any unified model must explain immune deficiencies too.

3.  Where do pro-inflammatory cytokine storms fit?  Are they upstream or downstream of the brain inflammation?  Do the pro-inflammatotry cytokines cause the brain inflammation, or does the brain inflammation lead to immune dysfunction and, thus, cytokine storms?

4.  Of course, it would help if someone could actually explain the external cause of ME/CFS, but I suspect we already know about as much as we'll ever know.  It's generally accepted that there are probably many doorways into ME/CFS: viral, bacterial, stress, traumatic injury, genetics, exposure to environmental toxins.  I think it will be a very long time before we're able to be more specific than that.

5.  Now that someone has developed a credible unified theory that actually makes a lot of sense (in my opinion), and after it's been tested, we've got to ensure widespread support for it from other ME/CFS experts.  We've got to somehow get all or most of these experts pulling in the same direction.  That step would require the concerted effort of an organization like IOM, or it would require one of the big-name researchers like Bateman to become a leader and rally the others behind her (if that's even possible).  This would likely be a very long process too.

6.  After general acceptance among ME/CFS researchers, this new model would expand and gain general acceptance among ME/CFS clinicians, and from there, spread to the greater medical community in general.  True, acceptance in the general medical community seems like a pipe dream now, but if there were a complete model that explained all of our symptoms and could be tested and confirmed, it would gain traction fast.  

(Remember the trajectory that the XMRV theory was on?  Imagine how quickly that knowledge would have spread among the general medical community if the findings had been confirmed.  They'd already be teaching it in medical school).

7.  I believe that only after there's a model of ME/CFS that truly gains acceptance in the general medical community will we ever see the major drug companies take a serious look at this disease and begin to develop drugs, in earnest, specifically for ME/CFS.   

Wild Speculation About the Future

When you consider all those steps, it can be a little discouraging.  Even if Bateman is 100% correct, it could still take as long as 20 to 30 years or more for these steps to occur.  Then again, sometimes progress doesn't occur in a linear fashion.  Progress sometimes builds momentum exponentially.  

Looking at the epidemiology of other diseases, often when one key connection is made, others are made very rapidly afterwards.  Imagine what would have happened had XMRV been confirmed.  Research money would have started pouring into our bare coffers.  Drug companies would have been racing to beat each other to the market with an XMRV anti-viral.  Our small circle of ME/CFS researchers would have likely expanded as other virologists and epidemiologists all over the world would have turned their attention to ME/CFS.  Progress would have accelerated very quickly for us. 

At any moment, we're just one breakthrough away from a rapid acceleration of progress.  Could Bateman's theory be the breakthrough?  Probably not because it's not a research finding...yet.  So far it's just a hypothesis.  But if and when it is tested, I believe it has the best chance yet of any hypothesis we've seen of being the breakthrough.

For now I'm simply glad that someone in a lab coat is finally looking beyond their own pet theory and trying to make sense of what their peers are doing too.  More of that, please!

Neuro-inflammation confirmed in ME/CFS.....again

Japanese researchers used PET scans to confirm a sort of "signature" type of neuro-immune inflammation that is only seen in ME/CFS patients.  File this under:  "things we kind of already knew but it's still nice to see confirmed again..."

http://www.riken.jp/en/pr/press/2014/20140404_1/ 

Detailed notes from the IACFS/ME Conference + Stanford Symposium

A friend of mine attended last week's Stanford CME Symposium and IACFS/ME Conference, and took detailed notes which are reproduced below with permission. My friend wishes to remain anonymous.  If you've been reading Seacher's summaries on Phoenix Rising, or Cort Johnson's summaries on Health Rising, much of this will be review.  However, for those that like to really "geek out" on this vital information (myself included), you will find additional details in these notes. Some portions of these notes have also been published on PR forums.

My friend attended the Wednesday Stanford Symposium, the Thursday IACFS patient session, rested Friday, and then attended the professional sessions on both Saturday and Sunday.

I want to thank my anonymous friend, plus Searcher and Cort Johnson, for the valuable information they provided us over the last week.  In some cases, they sacrificed their health to bring us these summaries. 

Warning:  This is long - it was 18 pages as a Word document. 

4/7/14 Edit: here are the same notes in a Google Doc for better readability

                                                            ____________

STANFORD SYMPOSIUM

MONTOYA MORNING SESSION: 

1. Case study with the researcher with HHV6:
1. There is a clear presence of virus during symptoms peak, as well as coronal flare and other brain lesions --> improved on Valcyte; but weren't in the blood after acute period (?)
2. anti-inflammatory treatment and anti-virals reintroduced
2. disease course usually fluctuates around a set point largely variable among patients
1. Gastrointestinal, cardiovascular/autonomic, neurological, intolerance of extremes to temperature
2. cardiovascular symptoms include: lightheadedness, exertional dyspnea, palpitations, POTS (postural orthostatic tachycardia syndrome)
3. Symptoms involving several organs, chronic, fluctuating, subsets of patients, evolution of disease over time
4. Stanford's approach: 
1. cutting-edge technology: high throughput technology to study immune system and genes (HIMC, Genetics department), exponentially increase the amount that we can measure (cytokines)
2. neuroradiology, EEG, cardiology, infectious diseases
5. thoughtful and compassionate care for CFS patients is possible
6. His heart goes out particularly to patients who are bedridden, crippled by disease, sensitive to stimuli
7. Stanford got involved as a response to the suffering experienced in solitude by millions of patients who have waited for an answer form the medical research community
1. Stanford’s first patient cohort exhibited a dramatic response to Valcyte
2. Valcyte has a degree of immunomodulatory effect - monocyte and neutrophil levels changed
8. current trial: use of a stimulant Methylphenidate/Ritalin --> this study needs to be tested at a very high level
9. scientific rigor (from Montoya’s mentor Jack Remington), candid approach, multidisciplinary, clinical and translational research
10. the Wild child French film -- CFS is analogous to the deaf mute child who no one understands
11. Clinic ~ 600 patients, waiting list 300 patients, new patients currently see his Physician Assistants
12. research efforts: multidisciplinary team, weekly executive and research meetings, recruitment for trials
1. external collaborators (Ian Lipkin)
2. case control studies: 200 CFS patients v. 400 healthy controls
3. in an attempt to determine whether circulating cytokines were associated with severity, a linear regression cytokine by cytokine analysis and adjusted for matched set
4. as disease progresses, progressive worsening inflammation (circulating cytokine profile)
5. IL-17 is a cytokine that has been associated with autoimmune disease (RA, IBD, psoriasis, experimental allergic encephalitis in mice and MS in humans)
6. in an attempt to determine whether cytokines were associated, LASSO used. TGF-B (anti-inflammatory cytokine, which inhibits activation of macrophages) related to duration of illness
7. progressive increase of cytokines with disease severity, and decrease of key anti-inflammatory cytokine
8. we believe that the data opens door to the treatment with anti-inflammatory agent
9. Double blind, randomized placebo trials (as well as interventions like sleep, meditation, anti-inflammatory)

1.      BETH UNGER FROM CDC:

1.      Areas of consensus for ME/CFS:

1.      Severe fatigue, unexplained, not relieved by rest, reduces activity

2.      PEM

3.      May be accompanied by co-morbid conditions such as fibro, IBS, TMJ, interstitial cystitis, migraines (pain syndrome)

4.      MCS, Lyme, Gulf War Illness

5.      Sleep, pain, fatigue all interact

2.      Areas of disagreement for ME/CFS:

1.      Duration of fatigue (6 months)

2.      Symptoms required

3.      PEM a required symptom or not

4.      Conditions that exclude diagnosis (medical/psychiatric conditions)  

3.      FUNCTIONAL IMPAIRMENT COMPARABLE TO CONGESTIVE HEART FAILURE, MULTIPLE SCLEROSIS, CANCER, DIABETES, AND LUNG DISEASE - CONSISTENT FINDING IN MULTIPLE STUDIES

4.      INABILITY TO ATTEND SCHOOL (as many of 1% who miss at least one day of school per week) à many of these young children have ME/CFS

5.      Decreased working memory and motor speed on neurocognitive tests

Jarred Younger's speech

1. ME/CFS study: Fatigue and Leptin
1. Primary hypothesis: leptin is correlated with fatigue
2. Some correlated strongly, others did not
3. Examine different cytokines --> leptin is the only one that significantly correlated with fatigue in the group
4. Machine learning algorithm used à IL6 and leptin correlated with fatigue --> model was 78.8% accurate
5. Leptin: appetite regulatory hormone, produced by white fat tissue, increases with obesity and stress-eating, inflammatory (ability to change immune system drastically)
6. Microglia: immune system cells in brain and spinal cord; serve as the primary defense mechanisms there; interact with neurons and lower their threshold to fire if something bad is happening; pushes brain into pro-inflammatory state --> sickness response like body aches and pain, fatigue, cognitive dysfunction
7. Microglia sensitized and becomes "PRIMED" –common causes including aging, exposure to diesel gas, chronic stress, immune hit, multiple immune hits à this process is similar to that which occurs in ME
8. Leptin serves as a microglia primer (activates at both a lower threshold AND much more vehemently)
1. If introduce leptin to cells, nothing happens
2. BUT in presence of leptin + hit by trigger, then cells (microglia) react much more forcibly
9. Some solutions:
1. Leptin-antagonists  (also low glycemic index, behavioral treatment like meditation
2. Microglia modulators: Naltrexone (worked well with fibro)
3. Chinese herbs that reduce leptin: panax ginseng, tumeric, resveratrol, gastodia elàinflexin (gastrodia elata??)
10. Subtyping of patients: most important things with CFS -- grant with 200 CFS women
11. Improving methodology (for example the use of saliva)

Amit Kaushal from Stanford on Genomics and bioinformatics with Ron Davis, Wenzhong Xiao: Analyzing Data at the Genomic Level

1. 200 patients meeting 1994 case definition v. 400 controls
1. Underlying heterogeneity, can we stratify the phenotype
2. 5 dimensions: general fatigue, physical fatigue, reduced motivation, reduced activity, mental fatigue
3. 20 questions total used in patient populations like cancer, fatigue
4. Correlation between MFI components for CFS subset: however, different subsets and different manifestations of CFS
5. MFI scores result (slides)
6. Gene expression: since we're testing 470000 genes, we can plot all these p values
7. Conclusion: large number of genes are different in CFS v. Healthy controls
8. Nextbio Disease Atlas --> the disease with the highest correlation was Systemic Inflammatory Response Syndrome
9. CFS seems to be a pro-inflammatory syndrome given all the cytokine lab results
10. Compared CFS with other datasets with inflammation: ubiquitin and immunoglobulin heavy chain, protein phosphatase, dynein, immunoglobulin, La antigen (Sjogren's antigen B)
11. Molecular differences between CFS v. Non CFS (Whole blood MRNA analysis)
12. Goal is to stratify the heterogeneous patient population, correlate with other CFS datasets (CyTOF and cytokine sets)

Dr. Montoya Talk ABOUT CYTOKINES AND DISEASE SEVERITY: 

1. measured 51 cytokines at the same time, 2 serums taken 2/day to control for variations
2. 2 sided independent t-test, linear regression, linear regression, LASSO method
3. cytokines are a highly interconnected network, so very complicated
4. Healthy control cases (similar ages, gender distribution, PEM was present in 96% of patients who met the Fukada criteria)
1. 26 cytokines decreased over time, associated with age
2. important because we need to control for age
3. cytokine differences between females (Leptin, ENA78, IL1RA, Resistin are all higher) v. males 
4. certain cytokines were higher in CFS v. control (abnormal, pro-inflammatory)
5. In an attempt to determine whether there was a correlation for cytokines with disease severity, the scientists plotted a LINEAR LINE
1. Healthy patients v. Sick: less cytokines
2. Montoya also treats toxoplasmosis patients in infectious diseases clinics
3. In toxoplasmosis patients dump cytokines during early stage of infection (immune system reduce cytokines in peripheral blood) –leading to a mild shift of cytokines from blood to tissue containing inflammation
4. As inflammation progresses in tissues, then cytokines spill over back to blood  (the theory!); other theory: initial stages – characterized by immune down regulation in the acute phase
6. 13 cytokines (these were identified as increasing with CFS severity) and as related to the following responses: cell trafficking, cell activation, cell growth and differentiation, cytokine production, Th1 v. Th2 responses
7. IL-17 = cytokine associated with autoimmune disease (RA, IBD, MS); 2 cytokines are also highly associated with females (sex ratio in ME?)
8. TGF-B levels are lower in patients who experience the illness for longer periods of time (it’s a powerful anti-inflammatory cytokine)
1. as disease lasts longer, the immune system loses its capacity to suppress inflammatory T cell responses 
2. progressive increase of cytokines + decrease of anti-inflammatory cytokine with disease duration à “a perfect storm”
3. PATIENTS’ BODIES INFLAMED, SENSITIVITY TO STIMULI AND PAIN --> supported by cytokines
4. 12 cytokines identified as having a dose response behavior
5. data opens door for treatment with anti-inflammatory agents (which treat other inflammatory diseases)
9. Question and Answer
1. Q what is the definition for "untreated" patient population?
2. A: no treatment for a year (no anti-microbials or antivirals)
3. *microglasia sensitivity increases with age

IAN LIPKIN TALK: 

1. Columbia’s team includes Dr. Mandy Hornig (director of the CFS program)
2. Koch's hypothesis: microbes are in every pathogen
3. Levels of certainty in Pathogen Discovery: If find evidence of microbe --> probable (causal relationship between exposure to microbe and disease) à a few more steps to ensure certainty
1. Entered the field through the AIDS virus situation; advocacy of the community changed the situation
2. detection of serum antibodies to Borna disease virus in patients with psychiatric disorders --  took 20 years to demonstrate no evidence for link between infection and disease
3. entry into CFS, since many at the CDC suggested Borna disease agent responsible for CFS
4. Zoonotic Diseases: (PowerPoint contained a map detailing zoonotic diseases)
1. looking at the animal kingdom for agents to cause human diseases
2. most important part of pathogen discovery: clinician who recognizes disease
5. Staged strategy for pathogen discovery: 
1. analytical stage: look across the tree of life (bacteria, viruses, fungi)
2. evolution of high throughput sequencing (Roche 454, Illumina, Ion torrent, Illumina Hiseq Xten) --> feasible to look at the host in the future as technology progresses
3. use linguistic/probabilistic approaches (analogous to the pathogen discovery process)
6. consistently look for new infections outside of humans too (many originate outside)
7. high frequency sequencing (next generation sequencing)
8. models for bacterium-triggered mental illness (like schizophrenia example)
1. CNS autoantibodies in mice exposed to group A Streptococci
2. took mice prone to autoimmune disease, immune stimulant injection and streptococci  bacterium implicated, and found that had the same syndrome with antibody regions in the brain, then pulled proteins from brain, micro-sequenced them, found the protein and cloned it, then demonstrated that humans and mice reacted to the same protein
3. model: move and integrate animal and human models
9. agent could be lurking anywhere, then invoke an immune response (hence the importance of the examination of antibodies)
1. toxins can be important as well, although present as infectious diseases
10. Not all infectious disease consults are for infectious diseases 
1. Plant in Minnesota processed pork, and originally considered it as an infectious disease
2. Air hose blowing the myelin out, so workers exposed to large amounts of CNS tissue and developed antibodies to it--> exaggerated immune response to these like an allergy response
3. it's not actually an infectious disease but immune response –consider in light of ME/CFS
11. technology uses: 
1. use Peptide microarray to find diseases
2. serochip results: 
1. use human samples exposed to various viruses (SAR, CORONA)
2. effective in finding the origins of the viruses (MERS-CoV survey of Saudi camels)
12. Kawasaki disease:
1. Symptoms include inflammation of blood vessels + fever (kids die if not treated with IVIG or electrophoresis? experience death by cardiac arrest)
2. association of Kawasaki disease with tropospheric wind patterns (7-20 miles above earth) 
3. (similar in multiple various agents for CFS)
4. During the experiment, things that seem sterile are NOT: Lipkin had to eliminate contaminants that confound 16s Analysis (in equipment); treat them by getting rid of the bacteria (use restriction enzymes)
5. look 10-2 days prior to onset of K disease
6. airplanes collected filters  à scientists conducted viral sequencing of filters’ particles in order to identify major pathogen dominant in these filters from China before they were dumped in Japan and America
7. lots of Candida species (a type of fungi) in the atmosphere
8. Kawaskaki disease resulted as ***an autoimmune response to environmental trigger!!  we need to consider this case study with regards to CFS**
13. Many with CSF have gut disorder –potentially address symptoms by treating gut
14. His theory: ME/CFS is very complex, scientists should stay open to a wide range of interpretations (but not psychosomatic!)
1. Discovery of tick-borne viruses by high throughput sequencing (maybe not just borrelia but another bacterium)?
2. Collected 500 ticks, characterized through high throughput sequencing and high PCR à wide variety of viruses à whether people with chronic Lyme react to these new viruses
3. When does clinical status changes, when titers for these agents vary
4. initially got into CFS with Dan Peterson in 1980’s
1. "absence of evidence of Borna disease virus infection in Swedish patients with CFS)”
2. the patients had immune activation
3. Although there was a false lead by Judy Mikovits with XMRV à Lipkin gives her credit because the hypothesis garnered support at the NIH for pathogen search
15. Chronic Fatigue Initiative
1. Plasma study: Masstag PCR and Consensus PCR screening: found 2 HHV6 positive, 1 parovirus B19 (control)
2. extracted Nucleic acid from 486 plasma samples, found HHV6 in 6 plasma samples (very small percentages)
3. retroviral reads present in 85% of sample pools (Montoya)
4. annelloviruses found in 75% of sample pools -- associated with immune suppression and commonly found in high throughput sequencing; respond to immune stimulants –but Lipkin doesn’t think annellovirus­­­­es will be helpful
5. Each time we don’t find a relationship, IT’S STILL AS HELPFUL AS A RELATIONSHIP! (rules out external pathogens)
6. 211 PBMC samples--13% samples positive for HHV6 but 11% controls positive for HHV6
7. Plasma cytokines in long and short duration ME/CFS (DATA ARE CONVERGING WITH JARRED YOUNGER’S STUDY): elevated levels of IL 17, other inflammatory cytokines
8. Spinal fluid showed lower levels of proinflammatory cytokine (difference in the CNS department v. periphery systems)
9. dramatic increases of cytokines in long-term v. short-term CFS
16. caution - modulation of the immune system is very dangerous
17. Batch effect in CFS (RNASeq Project); the way it is set up changes the dataset
1. in science, one has to be able to replicate data
2. messed up and had to redo the experiment
3. future CFS studies: RNA Seq, CFS gastrointestinal microbiome (progress), Metabolomics, Proteomics, High-throughput sequencing of PBMC (but need funding)
4. question - why not look at tissues if doctors have found enteroviruses and endogenous retroviruses elsewhere? they're not going to be the prime mover but set off an inflammation response  (like schizophrenia, MS)
1. the prodrome seems to be an upper respiratory infection
2. originally wanted to do fecal and PBMC samples 
3. microbiome that we should access should be relatively a-traumatic
5. Autism risk factors: 
1. bowel abnormalities in children with autism as high as 25%
2. GI therapeutic strategies - worth comparing to CFS patients with bowel disorders
1. Explains why children have difficulties processing some environmental toxins (NSAIDS, wine, etc)
2. if pregnant woman gets fever, higher chance the fetus develops autism. (genetic susceptibility and environmental factors)
6. has applied for an NIH grant for ME/CFS
18. colon cancer - right side is associated with weird methylation patterns - model for butyrate defiency in colon cancer; more fiber the healthier the gut biome (you are what you eat according to grandmother)

DR. MONTOYA'S Symposium Conclusion: 

1.      super momentum in determining the pathogenesis of CFS

2.      urgency to CFS NOW and our attendance is a testament to the urgency

IACFSME SF CONFERENCE 3/19-3/23

1)     Initial Approach to Management by De Paul’s Charles Lapp, MD

a)      Energy envelope: stay within the boundaries (symptoms worsen if body functions beyond current capacities, so overtime patient will restore energy, lessen pain and other symptoms, lessen illness severity)

b)     Think about person with Me/CFS as battery with 20% (envelope theory related to perceived energy)

c)      Buddy system improved in terms of vitality and energy conservation (vitality v. baseline/post treatment timeline)

d)     Helping individuals monitor and stay within energy envelope has helped levels of functioning over time

e)      Self regulate!!!!

2)     Charles Lapp from Charlotte, NC Treatment strategies

a)      4 cardinal symptoms: pain, cognitive difficulties, fatigue, sleep disruption (non-restorative sleep)

b)     Comorbidities: IB, IBS, migraine, Sicca/Sjorgen’s complex (dry mouth and dry eyes), POTS, Gluten sensitivity, Prostatosis, chemical sensitivities

c)      Standard addressing of symptoms (sleep, pain, fatigue)

d)     Managing sleep problems: suggested list of pharmacological therapies and non – pharmacological (rest, cold/heat packs, balneotherapy, massage, PT, chiropractic, acupuncture, ENS, EMS)

e)      Characteristics: exertional, positional, hypersensitivities, stress intolerance

f)      Plan for days of recuperation after exertion

g)      Can and must be active – objective limits of aerobic interval activity, heart rate limited, pedometer

h)     Therapies:

i)       POTS: water, salt

ii)     Modified Elimination Diet (avoid gluten, dairy, SCANT – sugar, alcohol, nutrasweet, tobacco)

iii)   Viral or immunological symptoms (Valtrex, inosine, nexavir, valycte)

iv)    Human growth hormone?

v)     Ampligen

vi)    Rituxan/rituximab; TNF alpha inhibitors

i)       Theoretical approaches:

i)       Coagulation defects

ii)     Marshall protocol

iii)   Nitric oxide

iv)    Glutathione/methylation deficiency

v)     Cardiomyopathy,

vi)    Toxic exposure

vii)  Stem cell therapy

j)       Final reflections:

i)       No known cause or cure

ii)     Most important to stay within limits imposed by intervals, heart rate, steps per day

iii)   Symptomatic therapy focuses on sleep management and pain control

3)     JOSE MONTOYA TALK – ANTIVIRALS!

a)      Herpes viruses are ubiquitous, infect a significant proportion of individuals and establish life-long latency

i)       Example of HHV6-stricken researcher, detected in blood and spinal fluid during height of researcher’s symptoms, but not presented in health controls

ii)     Herpes virus is a good candidate for the trigger of the illness

iii)   life-long latency – once infected, difficult to remove them from system

iv)    8 Herpes: HSV 1, 2, VZV (chicken pox), HHV5 (Cytomegalovirus), HHV6 and 7, HHV4 (Epstein Barr), Kaposi’s sarcoma associated with herpes (8)

(1)   When genital herpes recur, then symptoms flare with the activation

(2)   Herpes viruses have been known to activate even without obvious physical lesions

(3)   Disease model: herpes 2 is reactivated periodically in health individuals, goes into the spinal fluid, causes meningitis (without individuals being immunocompromised)

v)     Antiviral approach: Acyclovir, Famciclovir, Valtrex, IV ganciclovr, Valcyte, IV foscarnet, IV cidofovir, Combination therapy

(1)   Leflunomide (CMV IgG) – immunomodulator used in RA

(2)   Infusion of CMV specific T spells (sepsis patients)

vi)    Possible candidates for Antiviral therapy:        

(1)   Ascertain patient has ME/CFS

(2)   PCR positive patients

(3)   Oral Herpes HSV1

(4)   Genital herpes HSV2

(5)   Shingles VZV

(6)   High titers against EBV VCA, EBV EA, HHV6, HSV 1, HSV 2

(7)   HHV7,HHV 8 (very rare in America)

(8)   When everything has been tried, go with fluctuating but suggestive symptoms

vii)  Dose of antiviral regimen: give lowest dose then increase as tolerated

(1)   Remarkable worsening in the beginning phase

(2)   Is duration important? Longer valcyte treatment correlated with improved response

(3)   Trial published for 5 months acyclovir not effective

(4)   Valcyte results graph: cognitive function improved significantly; many patients OVEREXERT AND GET PEM

viii)Antiviral therapy of 2 patients with chromosomally-integrated HHV6

(1)   Improvement after foscarnet

(2)   Indicative that antivirals work for CFS patients, but difficult to determine WHO needs antivirals?

4)     Nancy Klimas talk on immunomodulatory medications:

a)      Exercise stress test first, then test for cytokines compared to baseline

i)       Dynamic challenge studies

ii)     Genomic results

iii)   RedCAP platform for assessment

iv)    Computational biology/modeling analysis with data scientists

b)     Publications: homeostatic drive in perpetuation of complex chronic illness – GWI and CFS

i)       After being pushed over, CAN YOUR BODY BE PUSHED BACK INTO BALANCE?

ii)     Mining Drug-action data

(1)   Reverse directory for drugs

(2)   for example, reverse TNF drug, test on animals/humans, potential repurposing of anti-TNFa Infliximab

iii)   95% of immune system is in lymph nodes and immune system

c)      Overview of the Immune Response

i)       Immune abnormalities:

(1)   Immune activation: DR, CD 26 expression

ii)     Functional defects (NK cell dysfunction, C8 cells)

d)     Immunomodulatory:

i)       Ampligen (both immune modulator and antiviral) but failed to pass FDA

ii)     biologic response modifiers (targeted approaches) – Humera

iii)   Rituximab (phase 2); deplete B cells

iv)    Alpha and gamma interferon (chia talk)

v)     Isoprinosine (Phase 2)

e)      Reducing inflammation:

i)       Omega3 quiets TNFa, LDNF reduces neuro-inflammatory pathways

ii)     Food and allergens

f)      Antivirals: help with immune exhaustion

g)      Immunovir (Newport Pharma), Inosine (OTC) à start LOW LOW LOW dosage and titrate up because people feel ill when clearing bugs so start with small dose

5)     Jarred Younger on Fibromyalgia:

a)      Fibro patients (25% improve over an 11 year period, 39% get worse)

b)     The problem of fibro: so many levels to examine – DNA, RNA, etc; is the problem in the muscles or the central nervous system?

c)      Most people believe: Fibro is a central sensitivity disorder, despite fact that you feel it in the body

i)       Analogy of a car alarm – everything including flying bird makes you feel horrible and sets off the alarm

ii)     Pain = bodily alarm system, most important sense, tells you when you’ve gone too far (tells you when you shouldn’t be doing this)

iii)   FIBRO: threshold dramatically lowered like getting groceries/gardening , faulty alarm system

d)     New research

i)       The flu – cytokine induced sickness response (body aches, fatigue, cognitive dysfunction, sleep disturbances, depressed mood, social isolation, headache)  à results from the immune system

ii)     Microglia (cell in the brain) – responsible for protecting us from everything

(1)   Looking for cell death, bacteria, viruses

(2)   Microglia activation: When find problem, change shape and pump out chemicals affecting neurons and changing the way their function (neurons fire and make you feel “sickness”)

(3)   With Fibro/ME/CFS, the microglia are the worst instead of the best in terms of the sickness response

(4)   Primed microglia (triggered when exposed to huge immune hit like Lyme, chronic disease, aging, opiates for long term use, obesity – release of leptin from fat cells)

(5)   Sensitized microglia: overexpress receptors, keep in active state, least factor will set them off and feel horrible

(6)   Issue: can’t test theory directly because too invasive. 

(a)    Doctors can’t get into the brain for direct testing of hypothesis

(b)   ANOTHER PROBLEM: when diagnosed with fibro, all other tests cease, so fail to do external tests (small fiber peripheral neuropathy, vitamin D deficiency, central nervous leak) so it’s important to continue to do tests

(7)   Day to day variability (how to track this?)

(8)   Also tracked leptin – as people’s pain increased, leptin increased

6)     Closing keynote speaker: The physician – patient relationship in the genomic era by Abraham Verghese

a)      What ET sees: rounds removed from the living patient, rounds centered around the iPatient, no need to examine patient, bedside = toxic, point of admission is to reduce 3d patient to 2d

b)     Joseph Leopold Auenbrugger – “new invention” book was seminal of its time

i)       Physician Jean Corvisart was physician to Napoleon Bonaparte

ii)     His student discovered the stethoscope

iii)   Back then the barber surgeons treated everyone, but the carrying of the stethoscope signaled to the world the transition from barber surgeon to physician; it was a moment with tons of discoveries of medical equipment

iv)    Luke Fildes: the doctor = seminal painting (child occupies the center of the painting, the doctor is in a passive; “I was ill and you cared for me” Matthew 25:30 à calls to the Samaritan functioning of being a physician)

v)     Stanford Medicine 25 Sessions – bedside manner with real patients (hands-on session)

vi)    Relationship between doctor and patient is a human-human exchange, embody the Samaritan qualities, human understanding, empathy, human skills

(1)   Straying from this = great disservice

(2)   Questions:

(a)    The success of alternative medicine is the abundance of hands-on interaction

(b)   How do you propose to get the computer out of the exam room? It mostly is related to billing, monopolize the system

(i)     Exposing the ludicrousness of this

(ii)   Lost privileges when didn’t complete the ICD coding training in EPIC (exemplified how the medical profession is so far removed from the patient experience)

(iii) Health care in America –ordering tests instead of examining and talking to the patient

(c)    Do patients have a role in treatment guidelines: if we have a doctor physician test to examine how to examine a patient (ACTUAL TEST V. MULTIPLE CHOICE).   Who determines whether the physician is accurate and detailed during diagnosis of illness – does anyone test Varghese aside from a MC choice exam?

(i)     The multiple choice test’s easy reproducibility is the main reason for its implementation NOT its ability to measure the effectiveness of the physician(compared to the drunk who loses his keys in the dark and looks for it in the light)

(d)   HIPPA: doesn’t see the point of it

(e)    Given the multi year wait list for Montoya, and the apparent urgency of ME/CFS as a field needing physicians, how do you propose a strategy to train future Montoya’s:

(f)    Answer: the dearth of physicians is related to reimbursement issues, what is societally-valued?    

(i)     CFS is not a sexy field to enter

(ii)   Long wait list due to how unique his treatment is

------------------------------------------------------------------------------------------------

Patient Adaptive Techniques:

Heart rate monitor

Pacing

Deep breathing through the stomach, (in through nose, out through mouth), tissue box on stomach

Fred Friedberg EDM Fibromyglia study

Day 3 and 4 of IACFSME

1)     Prevalence and Health-related Characteristics of ME and EMS/MCS – results from the Canadian Community Health Survey

a)      Summary: CFS is chronic and disabling, with little change in symptom severity over time

b)     Those with the most severe initial symptoms seem to have a higher likelihood of symptom improvement, although improvement does not necessarily mean recovery or markedly improved functioning

c)      Severe initial post-exertional malaise may be an important marker of functional outcomes and long term health status

d)     Onset type is not important in the long term course of CFS

e)      Episodic remissions occur in a reasonable proportion of CFS

f)      Patients have number of comorbid, chronic conditions 

g)      Acknowledgement­­: chronic fatigue initiative clinical epidemiology study subjects – Stella Lee, Komaroff, Bateman

2)     Aims: study prevalence of cancer in patients with CFS

a)      Specific conditions including fibro, sleep apnea, bunch of other comorbidities

b)     Chi-square analysis, principal factor analysis (14 conditions à 4 comorbidity factors)

i)       Anxiety, depression, PTSD

ii)     Hypothyroidism, autoimmune disease

iii)   Narcolepsy

iv)    Neurological disease

v)     Cancer

c)      Correlation and regression analysis

d)     Top 4 conditions: Fibro, depression, anxiety, hypothyroidism

i)       Comorbidities decrease odds of better health over time, and their participation of extracurricular activities, school, etc

ii)     Comorbidities increase odds of CFS symptoms worsening over time

3)     Lucinda Bateman: Evidence from a Multi-Site Clinical Epidemiology study

i)       Patient-identified effective treatments

ii)     Initial and current severity of 9 CFS symptoms from Fukada criteria + orthostatic intolerance

iii)   Results:

(1)   Self-help strategies 65% (rest including efforts to improve sleep and pacing, diet, exercise like strength conditioning)

(2)   Traditional medicine 53% prescription medications and vitamins, OTC medications, herbal remedies, acupuncture, massage

(3)   Dan’s clinic: traditional medicine listed as the more effective treatment of major symptomology of illness v. Bateman clinic: empower patients to live with this illness (self-help strategies, value and manage health over time) à

(a)    Variables that may reflect the clinic differences including patient age, stage of disease, location?

(b)   Autoimmune diseases (including hypothyroidism) more associated with traditional medicine (since that seems to help them the best)

(c)    Neurological diseases –>  complementary medicine     

(4)   Summary: self help and traditional medicine are the most effective treatment types in CFS patient population but vary in magnitude by site

(a)    Treatment type effectiveness varies by:

(i)     Severity of initial symptoms

(ii)   Initial symptom cluster severity

(iii) Current health status and functioning

(iv)  Remission (ever)

(v)   number of comorbid conditions

(5)   Cancer diagnoses by system: skin, blood, nervous system, thyroid, colon/liver/pancreas, kidney/bladder, breast, cervix/uterus/endometrium/ovary, prostate

(a)    Prevalence of any cancer: 15.5%

(b)   Excluding skin cancer, prevalence of any cancer: 8.1%

(c)    Prevalence of any cancer in US: 4.1%

(6)   Question and Answer session:

(a)    Q: how do comorbid conditions related with CFS compare to the percentages of the normal healthy population?

(b)   A: great question and study will result soon

(c)    Q: on neurological symptoms:

(d)   A: slides depicted mild improvements across wide range of the symptoms (including neurological ones); other epidemiology studies with more granular information about neurological symptoms are taking place beyond CFS community, but they can’t definitively make any statements about neurological symptoms specifically

(e)    Q: why does it seem that most of the highest improvements corresponds with the type of clinic (Peterson’s traditional medicine v. Bateman’s lifestyle and symptom management example)

(f)     A: It’s probably just the nature of medicine and how we treat patients and practice medicine

4)     Superior Ability of a 2-day CPET Protocol to Detect Functional Impairment in ME/CFS compared to either a single CPET, submaximal exercise test, or a VO2 prediction equation

a)      CFS frequently use these types of energy: they require frequent rest breaks

i)       Short-term anaerobic (to get up with fire alarm calls, brief)

ii)     Long-term anaerobic (15-75 sec)

iii)   VO2 peak measured directly during CPET is valid, standardized, reliable in health and diseased patients

(1)   Maximal effort CPEP exacerbates symptoms of PEM so use of submaximal test is of interest à get the necessary info without max testing them and crashing them

(2)   CPET 1: measures baseline functional capacity Vo2 peak and ventilator (anaerobic threshold), induces PEM

(3)   CPET 2: determine if patient can reproduce CPET 1 results within well-established normative data variability (not compared to a matched healthy control); very well established that these are repeatable tests

iv)    Accuracy of predicting Vo2 peak:

(1)   Linear relationship between HR and oxygen consumption (as workload increases, HR increase, O2 consumption increases in a linear fashion)

(2)   Predicted maximum HR = valid for all subjects (200 – age)

(3)   Constant work economy and mechanical efficiency during exercise

(4)   Normal day to day HR variation exhibited by patients

(5)   Prediction accuracy using submaximal HR has a standard deviation (standard error)

v)     The problem:

(1)   Detecting functional impairment requires accurate measures of functional capacity

(2)   Can functional impairment accurately be detected by Vo2 during 1 and 2 CPET tests?

(3)   Summary: measured vo2 peak using 1 CPET, 2 CPET, predicted Vo2 using validated ACSM cycle ergometer equation, predicted VO2 from submax HR

vi)    Subjects and Procedures:

(1)   Oxygen consumption (VO2), heart rate (HR), workload (work), respiratory exchange ratio (RER > 1.1), functional impairment determined

vii)  Results:

(1)    Predicted VO2 peak was higher than actual VO2 peak for both CPETs

(a)    CPET VO2 actual tests dropped significantly

(2)   Predicted higher than actual VO2 peak for both CPETS

(3)   Compared to health controls, PEM really lowers our ability to reproduce the tests

viii)Summary: Validated prediction equation consistently over predicts the VO2 max in Me/CFS patients

(1)   Interesting point: HR at three submax workloads are same for CPETS 1, 2

(2)   The linear relationship between HR, Work, VO2 are not maintained in Me/CFS with PEM

(3)   Regression showed poor ability to predict VO2 peak from any single or combination of variables

(4)   Submax HR-work relationship during CPET 2 did not reflect the 13% decrease in Vo2 peak (probably due to PEM)

ix)    Cardiac failure experiment – tried to test severity of impairment

(1)   43 % of sample appeared to have some degree of functional impairment on day 1 of SPECT, but when they were tested the 2^nd day, 67% met functional impairment criteria

(2)   Takeaway: using only 1 CPET, it failed to detect 15% of those with functional impairments – then the speaker said 55% (so confusing)

(3)   It’s dangerous to over predict VO2 because patient can overexert, or patient’s exercise therapy can be overprescribed

x)     Conclusion:

(1)   2 CPETS are required to accurately detect functional impairment in ME/CFS

(2)   1 CPET is sufficient to characterize functional capacity of ME/CFS or correlate functional capacity with other objective measures

(a)    However, assessment based on 1 CPET should acknowledge the inability of 1 CPET to detect deleterious effects of PEM on functional capacity in ME/CFS

xi)    DANGERS OF PREDICTING VO2 PEAK

(1)   It’s not linear so might over predict VO2 peak from heart rate à very dangerous for reasons such as the patient over working, the physical therapist making the patient push beyond limits

5)     Diminished Pulmonary Ventilation in CFS patients – effects of deconditioning and post-exertional malaise

a)      Definition of ventilation: when one breathes in O2 and subsequently removes CO2

b)     Results from exercise test day one and retest day two

i)       Huge similar reduction in ventilation at peak exercise and at the anaerobic threshold

ii)     Greater reduction in ventilation on test 2, especially at the anaerobic threshold à shows the PEM effect on CFS patient’s ability to exchange air

c)      Ventilator anomalies in CFS – what are they attributed to?

i)       Skeletal muscle fatigue? Oxidative deficiency?

ii)     Autonomic drive? Related to dysautonomia

6)     Introduction: Potential value of Exercise testing in ME/CFS

a)      Identification of measurable physiological markers to aid or confirm diagnosis or to help classify disability

i)       A drop in anaerobic threshold on the second day of exercise testing was present in ME/CFS but not in controls

ii)     Goal is to identify discrete subtypes within ME/CFS

iii)   Why submaximal exercise testing was used: screening for other disorders such as mitochondrial dysfunction, maximal cardiopulmonary exercise tests, test people without inducing a flare (CPET consistently causes flare)

b)     CONCLUSION: submaximal exercise testing procedure didn’t clearly distinguish between ME/CFS cases and healthy controls

i)       Subset of 19% of ME/CFS patients met criteria

ii)     Greater level of self-assessed exertion at lower exercise intensity experienced in ME/CFS might be explained by central perceptions (neurology component?)

iii)   Even submaximal testing was intolerable for a subset

7)     Examining Exercise Tolerance in CFS patients

a)      Retrospective study of 6 year exercise testing

i)       Cardiac output was monitored (pulse contour analysis)

ii)     Lactate levels

b)     Conclusion:

i)       peak O2 uptake is low in CFS patients

ii)     Circulation is not different

iii)   What explains the low values?

c)      What’s the underlying reason for this??

i)       ADP, Pi, and H+ are recycled in the mitochondria

ii)     Perhaps the cause of PEM is that several com­­­­plex biological pathways might possibly go wrong:

(1)   down-regulation of the entire system – lowering of lactate and H+

(2)   a block in the system resulting in lower lactate and higher H+ production

(3)   or something goes wrong in the mitochondria and the system compensates by overproducing H+ (protons)

iii)   low lactate after exercise in several patients –similar to another doctor’s work

iv)    I think the speaker said….”the problem is the low proton à low lactate consequently”?

d)     Question and Answer session:

i)       Q: what are your thoughts about a portable CPET machine to observe an individual’s given HR and VO2 max at any time while traveling, or during the specific moment of PEM after a particular exertion? A: The researcher owns such machine which cost $30,000 !!!

ii)     Q: do other patients outside of CFS have PEM?  A: Danish Dr. Vermeulen treated a HIV patient had PEM as well – second test a lot worse than the first test

iii)   Q: do you see other patients with PEM? A: No, and we have tested many patients with cardiovascular conditions etc, and they have nothing like CFS patients – both high and low functioning (yet the closest to the PEM was the HIV patient from that Dr. Vermeulen)

iv)    Q: What defines the minimal exercise threshold that induces PEM?  A: the patient – it has to be a very individualized approach to physical activity guidelines

v)     Q: there are potent PEM responses to CPET 1 and 2 testing… A: Researchers agreed that there was a concern

(1)   Some patients relapsed for 1 month

(2)   All docs need to be very cautious about the possibility of PEM

(3)   Patients need to expect a relapse and to be surprised if there is none

vi)    Researcher comments:

(1)   Lung-wise speaking: There was nothing wrong with the pulmonary function BEFORE THE EXERCISE

(2)   It’s the diminished functional capacity of the lungs itself WITH THE PEM AFTER EXERTION

8)     PET studies with CFS patients: sectors in the anterior cingulate

a)      Correlation between severity of disease and brain anterior cingulate

b)     Functional Somatic syndromes – doctor is investigating a whole constellation of syndromes

c)      Positive correlation between something in the brain + pain

d)     C-PK 11195 binds to the translocator protein, the index of activated microglia à when activated, translocator is upregulated and binding occurs

e)      Correlation between BP and attention impairment, yes there is neuro-inflammation according to Yamamoto

f)      Brain science of fatigue: PET imaging in the patients with CFS

i)       Overdepression of brain activity in CFS patients (overprotection) – for example, when patient is stimulated in one region, the auditory region is depressed….

ii)     Mirror system of Fatigue

g)      Fatigue and motivation – they are mirror images of each other (directly proportional)

h)     Neural circuits for fatigue: from acute to chronic phase (in beginning there is oxidative stress, cytokines, maybe something changes in the brain)

i)       Future studies  - start with healthy people, then go to CFS patients and needs to recruit many people

i)       Center for Health Science Innovation recently opened in summer 2013 – I think the speaker said 50,000 people recruited

ii)     Many partnerships in Japan (large centers of research)

9)     MARCIE AND MARK ZINN EEG AND CFS

a)      50 CFS patients, 50 matched controls

b)     Measures included 19 channel EEG, measured fatigue using the Multidimensional fatigue inventory, fatigue severity scale

c)      Examined Peak Alpha frequency – found that CFS people are lower in PAF (lower energy for energy and sensory inundation)

i)       Reduction in PAF activation, this widespread and in the absence of known cerebral lesions or head injury, usually suggests a deregulation of thalamo-cortical circuits

ii)     PAR and effects of fatigue: higher scores on fatigue are associated with lower PAF scores

iii)   Implication of reduced PAF in bilateral frontal, parietal, and central areas

(1)   Associated with interruptions in goal-directed behavior (coordinate cognitive functions in formation of coherent behavioral sequences ) – hard to keep it together

(2)   Parallels mental status changes – such as alertness and attention, decision making, etc

iv)    Conclusions: CFS subjects have lower PAF and correlation with fatigue and PAF

(1)   EEG can be used to evaluate the extent and nature of the brain disregulation once a CFS diagnosis has been established – as well as monitoring disease progression and treatment response

d)     IMPLICATIONS OF ABNORMAL BETA-2 SOURCES IN CFS: primary motor deficits, reduced responsiveness, slower motor performances, delayed reaction times, andmuscle weakness – hallmark features of CFS; sensory ataxia: reduced proprioception

i)       Disturbances in pain sensation, alterations in the process in go sensory stimuli (more generalized hypersensitivity) – instead of happening at the neocortical level, it’s like a more crude processing of stimulus

ii)     Slides also discussed reduced motivation  - hypofunctioning Broca’s area consistent with studies showing deficient verbal working memory and language deficits in CFS

iii)   Summary: global expression of CNS hpoactivation was found in CFS patients

(1)   Link between CFS symptoms and brain regions with quantifiable changes in brain state and function

(2)   These can be used to evaluate nature and extent of CFS –not a diagnostic but assessment!

10)  Q and A

a)      Some of the viruses (HHV6 and EBV) have an affinity for the brainstem, so the researcher is very interested and only recently has the tech enabled us to examine the brainstem

b)     Q: Are there other diseases with similar cognitive deficiencies in EEG; A: can’t use EEG purely as a diagnostic – only to confirm the diagnosis within the scope of other information and symptoms (like epilepsy)

11)  New international Primer:

a)      Revisions include the following: handouts for patients, index, sections on prognosis and mortality, expand section on severely ill patients, Pathophysiology: immune system changes, updated use of dietary supplements including CoQ10, acknowledgements, some typos

b)     Why a primer not guidelines?

i)       Guidelines limited to info found in systemic review of literature

ii)     Well received enough to be on the HHS website next to many guidelines

c)      All revisions brought to the entire authoring committee

i)       Statements appearing in the revised primer are conseus statmeents approved by the entire authoring committee

ii)     Committee: chair = Fred Friedberg, Lucinda Bateman, Lenny Jason, Lapp, Bested, Davenport, Staci Stevens, Rosalind Underhill, and etc

iii)   Arrangements made to translate the primer into French (the committee will reconvene about various translations)

iv)    Lily Chu: there is no evidence to say that ME is NOT fatal

(1)   There are no longitudinal studies of ME population to address this question

(2)   The one study cited in primer only had 600 sample size and was not tailored to this question

(3)   Rare cases where deaths attributed to ME

(a)    2005 Sophie Mirza was the first person in UK to have CFS listed as cause of death on certificate

(b)   Emily Collinbridge – died of ME at 31 in UK

(c)    Casey Fero – mother has ME, he died in 2003 at age 9 with cardiac arrest

(d)   Dr. Knox found higher risk of non-Hodgkin’s lymphoma in ME/CFS population; Sears study needs to be replicated

(e)    CFI – 4 fold increase of cancer rates in subjects

(f)    Suicides – should not be rated as second rate deaths, but many with ME who commit suicide aren’t depressed; but rather driven to suicide due to exhaustion based on daily struggle to exist

(4)   The “lack of mortality” statement – some providers might conclude that the patients are exaggerating the severity of the illnesses

(5)   IACFSME is the only international organization dedicated to CFS – everything has to be evidence-based, qualified statements, should be listed as an underlying not direct cause of death on death certificates; documenting mortality influences issues like research and funding; survey of deaths by Leonard Jason à contact them if interested in participating

(6)   Once information gets out, hard to correct

(7)   Question and Answer

(a)    Researcher found “presence root ganglionitis in patients” – inflammation within ganglion which sits outside the spinal cord (and is part of the nervous system) shown in autopsies

(b)   Lily’s experience has experience with filling out death certificates not pathology

(c)    Mortality is on page 26

v)     Q: How can we encourage health care practitioners to read the primer?   A: we need to get it out hardcopy so that physicians have the copy in office

vi)    State medical society – get on their program for annual meetings; get on the workshop for various practitioners like Physical therapists, General Practitioners, pediatrician

12)  Conclusion by Dr. Anthony Kamaroff

a)      Questions addressed by many of the presentations

i)       Is there evidence of objective underlying biological abnormalities?

ii)     Could these theoretically explain the symptoms and do they correlate with the symptoms?

b)     Huge New CFS Databases and Biosample Banks

i)       Nova Southeastern University/U. Miami/Miami VA Medical center

ii)     Stanford Medical School

iii)   Chronic Fatigue Initiative (multicenter)

iv)    NIH Multicenter Sutdy: Columbia University (*Hornig and Lipkin)

v)     UK ME/CFS Biobank

c)      Immunology Overview 1

i)       Elevated levels of allergy –associated cytokines and chemokines and other pro-inflammatory cytokines (*CFI)

ii)     Ability of other cytokines to separate CFS from healthy control (Stanford) – Jarred Younger findings

iii)   Stanford inflammation studies: levels of 51 inflammation –related molecules – cytokine family/chemokines/hormones measured

(1)   Unparalleled study even outside of CFS

(2)   Correlation of inflammation related molecule levels with illness severity!!! (as symptoms progressed in severity, linear correlation with the inflammation molecules)

(3)   Jarred Younger’s cytokine network – primacy of leptin (hormone discovered in 1994 made by fat cells and diminishes appetite)

(a)    Leptin is closely tied to immune molecule CYTOKINES – correlate with the levels of fatigue in CFS patients

(4)   Elevated levels of Interleukin -17 – strongly associated with autoimmunity; elevated IL 17 compared with T-regulatory cells makes the risk of an autoimmune diseases worse, suggests that autoimmunity playing role in CFS

(5)   Significant decrease in mRNA’s would increase PROINFLAMMATORY molecules -- > internal biological confirmation validating Younger’s findings

(6)   Elevated levels of interferon-gamma

iv)    Interferon-gamma and CFS

(1)   Released by lymphocytes in response to viral and intracellular bacterial infections

(a)    CFI study – a HUGE difference between subsets of patients <3 years and >3

(b)   Interferon-gamma correlated with cognitive impairment (frequently associated by intracellular bacterial or viral infection – suggests an underlying infectious agent)

v)     Telemoeres: ends of chromosomes, shorter in CFS patients than healthy subjects

(1)   Length = marker for cellular aging, shorter telomeres denotes cells aging more rapidly – the short cells has divided many times and is older, hence short telomeres = > increased vulnerability to variety of disease associated with aging like atherosclerosis

(2)   Life stress associated with shorter telomeres (parents carrying for sick children)

(3)   Telomeres are shorter in patients with CFS v. healthy à suggests underlying biological process that is making us age faster

vi)    Virology and Infectious Agents

(1)   CFI study – reported no microorganisms in serum

(a)    Q: what about circulating white cells, brain, other tissue?

(b)   A: we will be investigating these

(2)   Enteroviruses: Dr. John Chia –antigen and nucleic acid found in biopsies between CFS and controls

(a)    When you took biopsy specimens with enteroviruses and injected into the mice, you found enteroviral infection in mice

(b)   Indicative of an infectious agent (since mice were infected)

(c)    Impressive research, yet it is depressing that no one else has used the existing CFS biopsies to do this on a mass scale.  Dr. Komaroff hopes that it changes in the future

(3)   Public health /epidemiology

(a)    Canadian Community Health Survey estimates that 411,500 of 35 M Canadians (1.1%) have CFS

(b)   Nearly a third has experienced at least one remission, which had lasted 1 year (median)

(c)    Rest/exercise/diet are more likely to reduce symptoms than medications or alternative treatments

(d)   CFI study reported that patients more comorbid illnesses than healthy controls

(4)   Case definition

(a)    Need to be precise: the way each component (mild, moderate, severe) need to be specified

(b)   Empirically derived case definitions are superior to consensus-drive case definitions

(i)     Better at defining subgroups – use statistical subgroup through the big data

(ii)   Better at predicting an endpoint – prognosis, a laboratory finding thought to define the pathology of the illness­

(5)   Exercise provocation studies:

(a)    A stressor that makes a patient feel worse should also bring out the underlying pathology, and a 2x dose of stressor should bring it out even more

(b)   On a single exercise study CFS patients did not consistently perform below normal, a second test the next day found abnormal VO2 max in 9% patients – not even people with heart and lung disease experienced this degradation à in their experience, exercise physiologists haven’t seen this before, indicative of the uniqueness of PEM

(c)    Low peak oxygen extraction relative to increase in cardiac output

(6)   Pediatric CFS:

(a)    Surprisingly high prevalence of delayed milk protein sensitivity in kids – changing dietary patterns might be able to alleviate some of the suffering in kids

(b)   Combination of widely available/inexpensive laboratory tests may predict which people with mono go on to post-mono CFS

(i)     15 years of research show post-mono CFS

(ii)   WHICH TESTS ARE THESE?  Very inexpensive!

(c)    Depression was found only in 25% of pediatric CFS patients – even after onset of illness

(i)     Teenagers – background healthy sample’s prevalence of depression à15%, so it seems only marginally higher in CFS teens

(7)   Neurology:

(a)    qEEG changes in CFS – peak alpha wave frequency significantly reduced over 58% of cerebral cortex, delta wave frequency increased particularly in frontal and limbic areas of the brain

(b)   Correlated linearly with the SYMPTOMS (fatigue or pain)!! Validates the symptoms!

(c)    Indicating likely disruptions of information transfer across cortical networks, and inhibition of ascending arousal systems

(d)   Neuro-inflammation by PET Scan –

(i)     iv injection of compound that binds to a translocator protein in microglial cells and astrocytes, image uptake by PET scan à show increased signal in multiple areas of the brain

(ii)   Intensity of the signal correlated with cognitive impairment

(8)   Conclusion: yes, abnormalities in fact do theoretically explain symptoms and DO CORRELATE with the symptoms 

(a)    Case control studies comparing CFS to health and disease-comparison groups (fatiguing ones) find robust evidence of an underlying biological process involving brain and autonomic, immune system, energy metabolism, oxidative and nitrosative stress

(b)   Illness is not simply the expression of somatic symptoms by people with a primary psychological disorder

(i)     It was fair to ask 30 years ago to ask whether it was psychiatric stress, amplifying normal body sensations

(ii)   But today, it’s no longer a valid question!

(9)   Q and A

(a)    Q: are we at the point where we can have biomarkers?

(b)   A: EEG might be a biomarker, since it showed near-perfect correlation between CFS and healthy controls

(c)    Q: What about NK cells and biomarkers?

(d)   A: immune based biomarkers are reasonable places to define subgroups; Dr. Klimas believes confidently that NK cell function can be used to determine severity

[3/30/14 Update: Since posting this, I've come across some additional summaries of the IACFS proceedings from someone who I consider one of the best ME/CFS bloggers, Christopher Cairns. I was beginning to lament that the notes above don't include much on Dr. Chia's presentations, but Mr. Cairns has taken care of that.  His is a more editorialized account of certain lectures, which I find refreshing.  For more, please see:

http://cfspatientadvocate.blogspot.co.uk/2014/03/iacfsme-and-then-mission-delores.html

and

http://cfspatientadvocate.blogspot.co.uk/2014/03/dr-jose-montoya-and-stanford-mecfs.html ]

  

[4/3/14 Update:  Got 51 minutes to spare?  Health Rising posted a video of Dr. Komoroff's closing speech, which is traditionally a summation of all the presentations at the IACFS Conference.  http://www.cortjohnson.org/blog/2014/04/02/report-san-francisco-ii-komaroff-summary/]