All posts in Conferences

Is Chronic Fatigue Syndrome (ME/CFS) a Brain Disease? The 2016 IACFS/ME Conference Pt. III

December 23, 2016

brain chronic fatigue syndromeRemember:  $100,000 Year End Matching Gift Opportunity: A generous donor will match your gift to Simmaron between now and December 31, 2016, doubling your impact!

Chronic fatigue syndrome (ME/CFS) may be many things: an autonomic nervous system disease, or a disease involving the mitochondria, or an immune disease, but the IACFS/ME conference made one thing crystal clear – this disease effects the brain. Given the recent metabolomic findings suggesting that a low energy or hypometabolic state is present it makes sense that the most energy intensive organ of all – the brain – might  be affected. Plus, recent evidence suggesting that the brain’s immune system may be particularly affected suggests that brain might just be where it all comes together for ME/CFS.

In Part III of our 2016 IACFS/ME Fort Lauderdale Conference Overviews check out what the Conference told us about brain in chronic fatigue syndrome (ME/CFS).

Dr. Natelson: The Bad News / Good News Presentation

Dr. Natelson was in surprisingly good spirits given that he was delivering what must have been some wrenching news.  His recent study indicated he could kiss about a decade of work and one really interesting hypothesis goodbye.

A number of his studies had suggested that ME/CFS patients without mood disorders had more brain abnormalities (MRI’s, spinal taps, neuropsychological testing, lactate levels) than ME/CFS patients with mood disorders. It was an unexpected and exciting finding that was backed up by several studies, but the crucial larger study found no difference at all.

It’s certainly a cautionary tale regarding the small, generally underpowered studies that permeate this disease. Dr. Newton appears to have gone through a similar process; a stream of publications on muscle and mitochondrial issues were unfortunately later negated by a larger follow up study. It shows we can’t count on findings until they’re nailed down by bigger studies.

The news wasn’t all bad. Natelson’s latest study validated the fact that the major antioxidant in the brain – glutathione (GSH) – is lower in ME/CFS (we can accept that finding) and ventricular lactate levels are higher than in healthy controls (we can accept that one as well). Both findings would seemingly fit in well with studies showing that aerobic energy production is blunted and that neuroinflammation is present.  (We can’t accept the neuroinflammation finding yet.)

Dr. Natelson, a neurologist,  believes pro-inflammatory cytokines are probably whacking glutathione in ME/CFS. He also believes that reduced cerebral blood flows are a solid finding.

Occult Patients. About half the ME/CFS patients in his study also had two or more brain abnormalities – a condition Natelson called an “occult encephalopathy”. Occult refers to hidden or concealed abnormalities that take special tests to uncover. Encephalopathy is a broad term that refers to a syndrome that affects brain functioning. Natelson, then, has evidence (in what appears to be a fairly large study) that a hidden brain disorder is present in about half the ME/CFS patients.

Now that Natelson has evidence that a brain encephalopathy is present in about half the ME/CFS patients, he hopes to use proteomics to find a biomarker in the cerebral spinal fluid (CSF).  He’s preparing a grant proposal. This won’t be his first go-around in the proteomics field. Natelson was the senior author of the 2011 Schutser proteomics study which cast doubt on the idea that chronic Lyme disease is a subset of ME/CFS.

Natelson has high hopes for proteomics – a technology that he believes will help uncover unique biomarkers. In fact, Natelson, neurologist that he is, believes the hunt for a biomarker should begin in the cerebral spinal fluid, and then move to the blood. Because ME/CFS is, more than anything, a brain disorder, the best biomarkers are going to show up in the fluid that bathes the brain. They’re present in the blood too, but are being obscured by all the other factors in the rich broth that the blood is. His plan, then, is to locate them in the CSF and then find them in the blood.

POSTER – Zeineh Replicates Stanford Study

Zeineh’s arcuate fasiculatus results made a big, big splash when they came out in 2014. It was just a small pilot study, but it was Stanford, and that was enough for media outlets from CNN to Bloomberg News, the San Francisco Chronicle, and WebMD to lead with the news that ME/CFS is real.

I vividly remember Dr. Hyde, who knows of what he speaks regarding brain imaging, standing up at the Stanford Symposium and saying that was the best presentation on brain imaging in ME/CFS he had ever seen.

The Zeineh findings were exciting for a number of reasons. One, Zeineh used cutting-edge imaging technology called diffusion tensor imaging (DTI) that had not been used in ME/CFS before.  (One of the benefits of working at Stanford, Zeineh stated, was access to the best technology in the world.) We’ve always hoped that as medical testing gets more precise it will uncover issues that haven’t been seen before, and that’s what happened here.

The arcuate fasciculus is a connective fibe

The arcuate fasciculus is a connective fiber.

We know that the gross nerve damage present in multiple sclerosis isn’t present in ME/CFS, but we also know that the Simmaron Research Foundation’s cerebral spinal fluid study suggests that immune issues in ME/CFS patients’ brains may be almost as severe as those in MS patients.  Zeineh examined the brain’s microstructure, and his findings suggested that atrophy in the wiring that connects the different sections of our brain together had occurred. That kind of damage would impede the free flow of signals across the brain – making it more difficult to think and process information.  (Many brain diseases are now considered primarily diseases of connectivity.)

After his first study was released Zeineh pointed to its potential importance stating

“Most CFS patients at some point in time have been accused of being hypochondriacs and their symptoms dismissed by others. And there is still skepticism in the medical community about the diagnosis. That’s one of the reasons these findings are important.” – Michael Zeineh

Zeineh’s findings also suggested reduced white matter and problems with the thalamus and basal ganglia were present.  He attributed the fasiculatus results to inflammation.

Leptin Again..…Not only did Zeineh replicate his past results, but his ability to correlate them (in a preliminary analysis) with cytokine levels suggested that inflammation was indeed responsible for the damage he found. The real surprise, though, was the cytokine that popped up; it was leptin. With all the different cytokine results floating around (See the IACFS/ME Conference Immune blog) it was shocking to see a familiar cytokine pop up – and leptin at that.

Nobody had connected leptin to ME/CFS until Jarred Younger’s Good Day /Bad Day study suggested a couple of years ago that it was driving the immune problems in ME/CFS.  (Younger is in the middle of a larger validation study now.) Younger believes that leptin could play a key role in the neuroinflammation believed to be present in chronic fatigue syndrome.  Now Zeineh’s (preliminary) analysis suggests that leptin may be causing the brain injury he’s found. Although these results are preliminary, these are the kind of results this field could really use.

Zeineh has moved fast; he published his first study in 2014 and he presented the results of this study in 2016.

POSTERS:  The Zinn’s Damaged Connectome

Talk about connectivity:  the Zinn’s and Lenny Jason’s latest study found problems with connectivity in spades in what must be one of the most damaged brain networks of all in ME/CFS –  the attention network.  (Talk about a good fit for fatigued, concentration-challenged ME/CFS patients.) The Zinn’s found that the different brain-wave bands in this network were not in sync; while two were increased, another was decreased. Their small study also found significantly increased activation of three brain-wave bands in the attention network during a task relative to healthy controls. That actually wasn’t good news; it suggested that ME/CFS patients had to work VERY hard to maintain their attention during that task.

Connectivity issues came to the fore in the Zinn’s next poster as well. We know that information processing is slowed in ME/CFS. We also know that different regions of the brain have to work together to process information.  Put those together and it raises the possibility that the slowed information processing in chronic fatigue syndrome could be the result of bad connections.

transmission line

Reduced connectivity was the theme of several studies

Again, the Zinn’s small study suggests it just might be. Their EEG results pinpointed one brain-wave band that was inhibited across the occipital (rear), parietal (top) and temporal (front) lobes (i.e. a good chunk of the brain). Even worse the signaling “hubs” most effected in ME/CFS constituted “the most electrically active” regions of the brain.

A regression analysis also suggested that the longer you’ve had this illness the less well connected these parts of the brain are. The Zinns referred to their findings as “widespread functional dysregulation in the connectome”.

At the conference, Marcie Zinn pointed out someone vigorously talking to a group clustered around their posters. “That’s Rex Cannon, she whispered. It turns out he actually wrote THE BOOK on the type of EEG analysis they’re doing. The Zinn’s and Lenny Jason had apparently invited him down to the conference and he was interested; in fact he was so interested in their findings that they’re now collaborating with him.

Byron Hyde – the Pioneer

The “father” of brain imaging research in ME/CFS, Bryon Hyde, didn’t present but he was there and provided a nicely illustrated booklet on his findings. Hyde said he had a new book coming out on ME/CFS soon.

Hyde has been using SPECT scans to diagnose and treat patients for decades; his experience indicates that hypo perfusion or low blood flows to different parts of the brain is common in ME/CFS. Furthermore be believes that low blood flows to certain parts of the brain are causing many of the major problems in ME/CFS.  Simply by assessing a SPECT scan he can probably tell you what kind of patient you are.

In the booklet he demonstrated how he’s able to tie certain SPECT scan findings to distinct problems ME/CFS patients face.

  • Autonomic dysfunction – patients with autonomic dysfunction always, in his experience, demonstrate reduced blood flows in an area above the insular cortex called the operculum. The insula regulates homeostasis; e.g. the autonomic nervous system. Damage to this area is associated with orthostatic intolerance, blood vessel problems and problems with heart regulation.

Hyde, long associated with ME/CFS and critical of exercise therapies, is able to find middle ground with regard to activity. The damage to the insula and therefor to the autonomic nervous system is too significant, he believes, for these patients to benefit from graded exercise therapy (GET), but he also believes that patients shouldn’t let fear keep them in bed forever either. Depending on how severely ill a person is, Hyde states that “a gradual, patient regulated increase in activity is necessary, both for the body and the soul”.

  • Muscle dysfunction – Patients with muscle dysfunction show low blood flows to the motor cortex (Brodman’s area 4 of the posterior lobe).
  • Cognitive problems  – Patients’ problems with information processing (which included everyone), speech comprehension, and processing visual and auditory information – all have left anterior temporal lobe injuries. These are found in all ME patients.
  • Lots of Stuff –  Patients with problems in a host of areas including learning, complex motor skills (driving?), sleep, alertness, multi-tasking, emotions, etc. demonstrate low blood flows to the anterior and posterior cingulate lobes. Most patients have injuries in both these areas.

Hyde believes the 1984 Incline Village/Lake Tahoe outbreak investigated by the CDC was a classic enterovirus epidemic. He asserts in the booklet that Stephen Straus’ blockage of a publication about this outbreak in the New England Journal of Medicine by Dr. Peterson and others had tragic consequences.  Hyde believes that pure ME is an enteroviral disease diagnosed using disease history, gastric or GIT biopsy and a SPECT scan.

If Hyde is right about enteroviral infections, some hope may be on the horizon.  Enteroviral infections are so difficult to treat given our limited pharmocopia that most doctors don’t even test for them. Hyde reported, though, that several new enteroviral drugs (Pirodavir, Vapendavir, Pocapavir, Plecoaril and Rupintivir) are in the early stages of being tested.

Hyde has a new book coming out on ME soon.

Brain Research Heating Up!

A gateway to the brain - the cerebral spinal fluid

A gateway to the brain – the cerebral spinal fluid. (See the arrows)

Interest in neuroinflammation in chronic fatigue syndrome (ME/CFS) is growing, and that means more emphasis on the brain. The problems Natelson and Shungu have described (increased lactate, decreased glutathione and reduced cerebral blood flows) are likely the result of increased inflammation and oxidative stress. At the IACFS/ME conference Dane Cook demonstrated that exercise not only impairs cognition a day later but that it also puts a whopping damper on ME/CFS patients’ brain activity.

After Zeineh’s mighty diffusion-tensor machine uncovered microstructural damage in one of the main connective pathways in the brain, his preliminary analyses suggest that inflammation (via leptin) was the cause. Meanwhile, different issues with “the connectome” in the brain showed up in the Zinn’s (soon to be published) studies. Their tagging of the alertness network made perfect sense.

The brain research is heating up! Quite literally. The Solve ME/CFS Initiative just funded Jarred Younger’s attempt to assess neuroinflammation in the brain using a new heat scanning technique. Younger believes areas of the brain associated with fatigue are going to be red hot (figuratively speaking) in ME/CFS patients.

All these interesting results mean an increased interest in examining our best gateway to the brain (short of a biopsy): the cerebral spinal fluid (CSF). As was noted, Dr. Natelson is eager to get underway with his proSR_Donate_6.9.14_1teome CSF study. Dr. Baraniuk is currently examining the exosomes – small fluid vesicles that contain inflammatory factors – in the CSF of ME/CFS patients to see if they’re adding to the inflammatory milieu there. The Simmaron Foundation’s new spinal fluid study, which is incorporating Dr. Naviaux’s metabolomic results, aims to duplicate and expand on its past CSF study.

That study showed a degree of immune dysfunction almost equal to that found in multiple sclerosis. Remarkably, almost half the cytokines in the ME/CFS patients were abnormal. No exercise was needed to tweak them. There was no need to filter for duration or severity either. Even at rest those cytokines were off, off, off.  That suggested that major and readily identifiable immune issues exist in the brain. It also suggested, as Dr. Natelson proposed, that the brain might just be the first place researchers should go to look for immune problems in ME/CFS.

Given the variable cytokine results often seen in this field, it was stunning to see the Simmaron Foundation’s CSF cytokine results essentially duplicate those found in the Lipkin/Hornig blood study. That got Ian Lipkin so excited that he flew all the way to Incline Village to promote it last year. Simmaron is raising money for that project right now.

Remember:  $100,000 Year End Matching Gift Opportunity: A generous donor will match your gift to Simmaron between now and December 31, 2016, doubling your impact!

SR_Donate_6.9.14_1

Simmaron Foundation’s Immunology Workshop: the Forefront of Diagnosing and Treating ME/CFS

Simmaron’s Immunology Workshop on ME/CFS, Part I

survey

Immunologists came to the Simmaron Foundation’s Immunology Workshop to decide if immune tests should be standard practice in ME/CFS diagnosis and treatment

Immunologists came to the Simmaron Foundation’s Immunology Workshop to decide if immune tests should be standard practice in ME/CFS diagnosis and treatment.

Simmaron Research Foundation is focused on redefining ME/CFS scientifically. They produced the Immunology Workshop at the 2014 IACFS/ME Conference in order to get a consensus from immunologists and practitioners on whether immune testing should help guide diagnosis and treatment in Chronic Fatigue Syndrome (ME/CFS). Immunologists were invited to give presentations and then queried regarding whether immune tests should be incorporated into diagnostic protocols for this disorder.  Dr. Unger, the head of the CDC’s CFS program, was invited to attend.

Overviews of  some of the presentations make up Pt I of the Immunology Workshop Overview.

(I used my notes from the Workshop to build the foundation for this blog and then expanded on many of the subjects presented; i.e. the blog reflects my interpretation of the presentations and what they mean; it may not in places reflect the presenters viewpoints.)

Troy Querec, Ph.D, CDC – Natural Killer Cell Testing 

The CDC ignored natural killer (NK) cell functioning in ME/CFS for many years, but they appear to be convinced now that it’s a key problem.

Natural killer cells are called ‘natural killers’ because they don’t need to be activated to kill cells that don’t have the right MHC markers on them. They are also the only immune cells that can recognize infected cells without antibodies and MHC markers being present.

medical tests

The NK cell function test that reveals how effective NK cells are at killing invaders is laborious, expensive and, according to an NSU presentation at the IACFS/ME conference, not suited to most labs.  (This isn’t the first immune test relevant to ME/CFS that has not been readily available. Most of the tests associated with the RNase L enzyme are still available only at one lab in country.)

Recognizing the need for your average doctor to have access to a less expensive test of NK cell functionality, the CDC is working on one. (They’re not the first. The Klimas/Fletcher group in Miami was reportedly working on one several years ago.)

They’re focusing on measuring how effective the receptors found on the surface of NK cells are at turning the cells on. Receptor deficiency could play a role in the poor NK cell functioning found in ME/CFS. To that end they’re developing CD 107 antibodies that attach to the receptors.

Because shipping has also been shown to reduce NK cell viability, they’re also proposing ways to optimize NK cell viability during the shipping process. This involves keeping cells in their natural habitat – the whole blood – and isolating PMBC’s first. They propose a pilot study to determine ways to optimize viability of NK cells during shipping.

Finding an easier and more effective way to measure NK cell functionality would go a long way to establishing NK cell dysfunction as a biomarker for ME/CFS.

Dr. Constance Knox – B-cells and Chronic  Fatigue Syndrome

“Lots of vacuums in this field” 

After noting how little we know about the role B-cells play in ME/CFS, Dr. Knox echoed Mady Hornig’s statements that there are “lots of vacuums in this field” and then went onto a short overview.

A cornerstone of our immune defense, B-cells directly ‘attack’ pathogens and trigger other parts of the immune system to respond.

B_cell_activation

B-cells could be a major contributor to ME/CFS but the role they play is largely a mystery

First, they are activated by antigens (proteins associated with pathogens) brought to them by macrophages and dendritic cells – two innate immune cells. B-cells then produce hordes of pathogen specific antibodies that search for the pathogen outside the cell and attach to it in order to prevent it from attacking our cells. They also take that antigen and present it to killer T-cell’s which then mount a pathogen specific defense which gets at pathogens located inside the cell.

Two recent findings have overturned medical dogma concerning B-cells.

Naturally Occurring Antibodies: At one time it was thought B-cells only produced antibodies that were directed at specific invaders, but it’s now clear that naturally occurring antibodies – which are not directed at specific pathogens – are present as well. These antibodies are derived from unusual sugar residues synthesized in the gut – an interesting finding given the emphasis both Dr. Hornig and Dr. Lipkin place on the gut in ME/CFS.

Regulatory B-Cells – Cells regulating the powerful T-cell response (T-regulatory cells) received most of the attention until regulatory B-cells were discovered. Regulatory B-cells make up only 0.5% of total B-cells but are powerful regulators of immune activation and inflammation. They induce two important anti-inflammatory cytokines (IL-10, TGF-beta), which dampen the inflammation produced by the innate immune system.

b-cell signaling

Problems with B-cell signaling would pose problems for other parts of the immune system.

IL-10 restores Th1/Th2 balance (a problem in ME/CFS) and inhibits inflammatory cascades while TGF-B wipes out some types of T-cells, dampens the activity of cytotoxic T-cells, and takes other actions to reduce inflammation. These cells often get upregulated in states of chronic inflammation and elevated levels of both have been found in ME/CFS.  (They suggest the immune systems of ME/CFS patients are attempting to reign in inflammation.)

Research  is need to determine if either cell plays a role in ME/CFS, but several ongoing studies may give us clues regarding the role B-cells play. Rituxian (Rituximab) – an monoclonal antibody directed against mature or activated B-cells – reduces B-cell numbers. (A successful result in Rituximab trial could indicate B-cells in ME/CFS are triggering an autoimmune response or could implicate EBV infection.)

A 2011 study documenting increased rates of lymphoma in ME/CFS patients suggests more problems with B-cell regulation may  be present in a subset of  patients.

David Baewer, M.D., Ph.D – Serology and HHV-6 Infections

Most humans carry latent herpesviruses in their cells that do little harm. Once activated, though, in people with poorly functioning immune systems such as transplant patients, these seemingly innocuous viruses can cause enormous damage. With their immune systems intentionally knee-capped in order to avoid an immune attack on their transplanted organ, they are ripe for herpesvirus activation. Several antivirals under development that could assist some people with ME/CFS come from research devoted to preventing herpesvirus activation in transplant patients.

herpesvirus

Some researchers believe herpesvirus activation is common in ME/CFS -but that the typical virus tests are not up to the job.

Dr. Baewer proposed that the same  general processes causing herpesvirus reactivation in transplant victims is occurring in ME/CFS. Standard testing for herpesviruses, however, is unable to distinguish the kind of active herpesvirus infections he believes are present in ME/CFS.

He noted that primary active infections – which occur when the body is first introduced to a pathogen – are often diagnosed via a high IgM response.

The kind of herpesvirus infection suspected in ME/CFS, however, (and the kind that mostly occurs in adults) involves reactivation from a latent infection. Because these kinds of infections rarely generate a robust IgM response, Dr. Baewer asserted IgM readings in adults have little clinical value.

Viral DNA with PCR isn’t effective either because it only tells us if the virus is present and it is present in 95-100% of population.

Viral mRNA using reverse transcriptase PCR, on the other hand, shows whether the virus replicating or not.  This type of testing tells which genes in herpesvirus genome are present in the blood – and identifying which genes show up is the key to determining whether the virus is actively replicating or not.

Herpesviruses need to be able to attack and establish themselves in B-cells, ward off the immune system’s efforts to find them and then replicate when the time is right. They are complex viruses with big genomes that have genes associated with maintaining latency, with altering the immune response and with building new viruses. Viral mRNA using reverse transcriptase PCR can identify which stage the virus is  in.

gene

Tests can reveal which stage of its lifecycle EBV is in. Unfortunately, those tests are rarely done in ME/CFS patients

If there is evidence of genes associated with latency, but nothing is present, the virus is simply maintaining latent state. If genes produced later in its life cycle are found, the virus is active but not replicating. If genes devoted to building the outer membrane of the herpesvirus are present – you have an active, replicating virus on your hands.

(The fact that Epstein-Barr virus can hijack the nuclear machinery in B-cells and go through its early, medium and late cycles without ever replicating suggests it can cause much mischief simply sitting in B-cells.  We know that in order to maintain latency, EBV affects how B-cells, a critical part of the immune machinery, function.  We know EBV increases the lifespan of B-cells and that it prompts them to replicate. Some researchers believe EBV’s effects on B-cells underlie all autoimmune processes in the body. )

The smoldering herpesvirus infection hypothesis in ME/CFS produced by Dr. Lerner and researchers at Ohio State University proposes EBV is perturbing immune cells and causing immune cell dysfunction without causing cell death, while producing only very low levels of viral transcription.

Because herpesvirus serology tests will not pick up this type of infection, however, it will never be picked up by standard serology tests.

(to be continued…)___________________

simmaron logo

The Immunology Workshop – Redefining how ME/CFS is diagnosed and treated

Simmaron’s Immunology Workshop Participants

  • Daniel Peterson, M.D. Sierra Internal Medicine, Incline Village, NV
  • Nancy Klimas, M.D. Ph.D Nova South Eastern University, Miami, FL
  • Paula Waziry, Ph.D Nova South Eastern University, Miami, FL
  • Sonya Marshall, Ph.D Griffith University Gold Coast Australia
  • Sharni Hardcastle, Ph.D Griffith University Gold Coast Australia
  • Konstance Knox, Ph.D., Founder, CEO, Coppe Healthcare Solutions
  • David Baewer, M.D. Ph.DMedical Director, Coppe Healthcare Solutions
  • Isabel Barao, Ph.D., Research Assistant Professor, University of Nevada, Reno, Simmaron Research Scientific Director
  • Gunnar Gottschalk, B.S., Simmaron Research, Incline Village, NV
  • Troy Querec, Ph.D., Associate Service Fellow, Centers for Disease Control and Prevention, Atlanta, GA
  • Dennis Mangan, Ph.D., Former Chair, Trans-NIH ME/CFS Research Working Group, Office of Research on Women’s Health, U.S. National Institutes of Health
  • Mary Ann Fletcher, Ph.D., University of Miami Miller School of Medicine Professor of Medicine, Microbiology/Immunology and Psychology
  • Elizabeth Unger, M.D. Ph.D., Chief, Chronic Viral Disease Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases. Centers for Disease Control and Prevention, Atlanta, GA

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


[1]

Report From San Francisco I: The “Father of Autoimmunity” Speaks

March 31, 2014

When the "Father of Autoimmunity' went to medical school 'autoimmunity' was not believed to exist

When the “Father of Autoimmunity’ went to medical school ‘autoimmunity’ was not believed to exist

Dr. Noel Rose M.D., PhD is  the Director of the Center for Autoimmune Disorders at Johns Hopkins University. Dr. Rose has been studying autoimmunity for over sixty years  but he was a pretty darn spry 80-something at the conference.

When I got close enough to  ask him a  quick question I would have sworn he was a well-preserved sixty something. The bow tie,though, still apparently in  fashion in some medical circles, gave it away as did his statement that the medical schools of his day scoffed, yes, scoffed at the idea that the body could attack itself.

In fact, in 1956 Dr. Rose was the first researcher to introduce autoimmunity as a cause of disease. In an interview he stated

“They were skeptical. People weren’t really prepared to believe it because it seemed so bizarre that you would develop an immune response to your own body. We had all been taught in medical school that the immune response is only directed to what’s foreign. But now we know that isn’t true.”

He’s one of the few people who could can say they wrote the book on it because he did. He wrote the first book on autoimmunity and it’s still being revised today. (Get the latest 1300 page edition for a cool $215)

Dr. Rose probably didn’t appear to know a lot about Chronic Fatigue Syndrome, but he does know  a lot about autoimmunity and with the Rituximab trials putting that subject on everyone’s mind it was good to get a primer on it.

Dr. Rose started off explaining the basics of the autoimmune response by stating that it’s a completely  natural response. We’re all doing autoimmune responses all  the time.  The reason for that is that ‘we all’; that is all the organisms on earth,  share proteins and enzymes and that means that the immune system is going to, in its fervor to rid the body of a pathogen, will inevitably accidentally attack the body instead at times. That means we  come loaded from the get-go with auto -antibodies and  self reactive T and B-cells and also that  we have a built-in way of suppressing those cells.

It’s when that suppression system goes down that you have trouble.

Males and females generally have equal rates of autoimmunity until puberty when the hormones kick in. Rates begin to even out  more in seniors

Males and females generally have equal rates of autoimmunity until puberty when the hormones kick in. Rates begin to even out more in seniors

An autoimmune response can affect essentially any organ disease in the body, and while  autoimmune disorders can show up very differently, they also share many features. They’re common – they’ve been diagnosed in about 20 million people in the U.S., but probably closer to 50 million Americans have one. They’re ‘chronic’  (usually life-long). They mainly affect women and they’re heavily hereditary.

There are no known cures, they’re expensive – costing the U.S. about a hundred billion (gulp) dollars yearly, and, in contrast to cancer and heart disease, they are on the rise.  About 80 autoimmune diseases have been identified and more are coming.

To the question why there are so many autoimmune  diseases, he stated

 “We think it’s the fact that the immune system is always looking for new pathogenic organisms and being very broad in its abilities to recognize organisms that it also responds to things within our own bodies that are of the same or a very similar substance.”

 

The Sex Bias

Hormones clearly play a major factor in the female predilection for autoimmune disorders.  Rates of autoimmune disorders in children  prior to puberty are equal  in males and females and pregnancy can have a huge effect on symptoms, with some women feeling much better.

They’re believed to  mostly result when  a genetic weakness plus an endocrine effect (female bias) bumps up against an environmental trigger such as an infection. Bad genes account for thirty percent of  the risk which means that 70% of it is probably some chance environmental factor you would have surely avoided if only you’d known.

Known environmental triggers include viruses (in particular EBV), bacteria (streptoccocus), drugs, foods (excess salt), pollutants such as mercury, hormones, stress (important but hard to quantitate). Because the exposure usually comes months or even years before you come down with an autoimmune disorder finding, the triggering factor is  often very  difficult.

gene

Genes account for 30% of the risk for getting an autoimmune disorder. Environmental triggers (infection, toxin, stress, drug) are far more important.

Celiac disease is one of the few autoimmune disorders in which the triggering factor is clear: gluten. Gluten-free diets may be important for more than Celiac patients, however. Dr. Rose believes they  can help people with other kinds of autoimmune disorders.

“Interestingly,” he added, “the gluten free diet may also be helpful for people who don’t have celiac disease but who have other forms of autoimmune disease. It’s just speculative, but as gluten free diets are more available, other people are trying them and often feel better.”

If you have a family member with an autoimmune disorder your risk of developing one jumps over 10-fold (from  .4% to 7%). If your twin has an autoimmune disorder you’ve got a 30% chance that you will come down with one  as well.

Once autoimmunity gets going it usually causes more damage and inflammation and generates more autoimmunity. One of the common signatures is  multiple autoantibodies to multiple antigens.

Treatment

Like ME/CFS and many other chronic illnesses, treatment is focused on symptom alleviation not curing the disorder. Progress is being made, however.

 “We still don’t have a cure, but new treatments have been introduced in the past 15, 20 years for autoimmune diseases like lupus and MS that are remarkable and very much improved. As we understand more about the autoimmune response we find more ways of developing drugs that will intervene, that will benefit the patient by at least alleviating the symptoms even if they won’t cure the disease.”

Autoimmune or Autoinflammatory?

Some disorders that have a strong inflammatory component and look like autoimmune disorders  are not auto-immune disorders; they’re auto-inflammatory disorders.  People with the autoinflammatory disorders carry  loads of auto-antibodies, but lack the self-reactive T and B cells found in true autoimmune disorders.  With regards to treatment  it’s often  a distinction without a difference because both involve the  innate immune system and they’re often  treated the same way.

innate immune diagram

Problems with the innate immune system (NK cell, neutrophils, complement, histamine, etc. ) are behind autoinflammatory disorders

The term  autoinflammatory only showed up in the scientific literature for the first time in 1990’s. Autoinflammatory disorders involve dysregulation of the innate immune system (NK cells, dendritic cells, macrophages,etc.) that result in high rates of inflammation.

Autoinflammatory disorders originally included ‘recurrent fever syndromes’, then branched out to include some genetic disorders, hard to understand disorders like Crohn’s disease, and now may include such common disorders as type II diabetes, gout and atherosclerosis. The  decreased adaptive immune response and increased innate immune response found in autoinflammatory disorders suggest aging could be included in this category. (In the Conference we’ll see some preliminary evidence of increased aging in ME/CFS)

We don’t know if some  individuals with ME/CFS have an autoimmune or an autoinflammatory disorder. Rose didn’t appear to know much about ME/CFS but after his  talk I asked Rose what I thought was THE question; the question that was not given to him  during the Q&A session even though I wrote it out twice,  the second time at least semi-legibly, and  that was:

“What does a positive response to Rituximab in a gender  specific disorder tell you about autoimmunity or  an auto-inflammatory response?” The MAN said it meant it could be either.

 ME/CFS Autoimmune Studies Underway

 “We hope this study will identify a pathogen as a likely causative agent of the disease in order to focus future study. Dr. Elledge

dorsal root ganglia

One CFIDS Association of America study will target autoantibodies to the dorsal root ganglia that the Light’s believe play a role in ME/CFS

Besides the two Rituximab trials two studies, both using the CFIDS Association of America’s Biobank, will shed light on the role autoimmunity plays in  ME/CFS. One promising study lead by Dr. Elledge of Harvard University will determine what the autoantibodies present in ME/CFS patients blood are targeting and what viruses the antibodies present are associated with.

“…autoantibodies to brain and dorsal root ganglia have been demonstrated in chronic post-Lyme disease syndrome, an entity essentially identical with chronic fatigue syndrome/fibromyalgia” Dr. Cooperstock

Another lead by Dr. Cooperstock will look for autoantibodies to nervous system targets including the dorsal root ganglia that feature in some theories of ME/CFS.

Simmaron’s Immunology Workshop at IACFS/ME: Redefining How Chronic Fatigue Syndrome Is Diagnosed and Treated

Immunology Primer For Practitioners

I’ve been going to IACFS/ME conferences for eight years now and I’ve never seen a Workshop like this. This is a Workshop that could change how Chronic Fatigue Syndrome patients are tested and treated in the upcoming years. Called the “Immunology Primer for Practitioners“, it’s chaired by Dr. Daniel Peterson.

key

Standard immune tests for ME/CFS patients could change viewpoints and unlock new treatment opportunities for many.

It’s mission: to produce bulletproof recommendations for immune tests that will guide both the diagnosis and treatment of chronic fatigue syndrome. Doctors are interested, patients are surely interested, and Dr. Unger from the Centers for Disease Control (CDC) is interested, so Simmaron Research is seizing the moment.

Recognizing the opportunity and realizing that a consensus recommendation of experts would carry the most weight, Simmaron gathered 12  experts (sponsoring half of them), including nine immunologists, to produce ironclad recommendations.

Redefining ME/CFS Indeed

The Simmaron Research Foundation is committed to ‘Scientifically Redefining ME/CFS’ and  few things could change the landscape more rapidly for patients than the CDC including immune tests in its ME/CFS management guidelines.

We know common blood tests reveal little or nothing about ME/CFS, but  immune tests may not only be very revealing, but may open the door to a new conception of ME/CFS in the medical community, and to a whole swath of treatments most MD’s know little about.

Producing Real Change

vision

Simmaron is committed to funding work that alters how the medical profession sees and treats ME/CFS

In order to produce real change you need to get at the ‘levers of power’ and, like it or not, the CDC is one of those levers. The CDC is trusted by gatekeepers in the medical field. It’s recommendations matter. As we know, for better (in this case) or for worse (in the past), they get spread around.

Dr. Unger’s interest in immune test recommendations from ME/CFS experts is just the latest in a series of transformative moves at the CDC.  Instead of holding ME/CFS experts at arm’s length, Dr. Unger has embraced them. She has visited many of the experts’ centers, and her multi-year, multi-site clinical assessment study is bringing the insights of ME/CFS experts to the fore at the CDC and other agencies for the first time.

The Latest in Immune ME/CFS Research

Besides the recommendations, the Workshop will provide education for clinicians on the immune system in ME/CFS, overviews of immune findings, and insights into cutting-edge ME/CFS immunological research. We will hear highlights from the Australian NCNED teams intense focus on natural killer cells, learn what the  CDC is currently researching, uncover what very severely ill ME/CFS patients’ immune system looks like, understand how herpesvirus infections might be linked to autoimmunity and more.

The immune system features prominently in this years IACFS/ME Conference

The immune system features prominently in this years IACFS/ME Conference

Underscoring the strong immunological focus in this IACFS/ME Conference, Dr. Peterson’s session follows an opening presentation by Dr. Ian Lipkin.  Dr. Lipkin described evidence of “ongoing stimulus to the immune system” and a different immune profile  patients ill less than 3 years have compared to long term patients last fall on a conference call hosted by Dr. Unger.

Dr. Klimas’ panel the next day will go deep on “The Latest Research in Immunology”, including results from Dr. Lipkin’s collaborative research, the CDC’s genomic study, and Dr. Marshall’s natural killer cell research. Her panel follows the Plenary Session with Dr. Noel Rose, Director of the Center for Autoimmune Research at Johns Hopkins.

It is a pivotal time in ME/CFS, and immunity and autoimmunity are coming into focus. Simmaron seeks to take these groundbreaking sessions into clinical practice with consensus.

Simmaron Research Foundation Moving Forward

Yes

Redefining ME/CFS step by step

This is just one of the Simmaron Foundation’s efforts to redefine Chronic Fatigue Syndrome by taking advantage of the expertise and experience of Dr. Peterson and his fellow practitioners.

That effort began with Dr. Peterson’s retrospective analysis of treatment success using Vistide in selected patients and will continue with further analyses of the effects of other immune-based treatments, like IVIG and Ampligen.  Dr. Peterson will also be participating in the B-12/MFTHR trial this spring.

In order to address a critical need for more expert  ME/CFS clinicians the Simmaron Foundation has also funded a practitioner to learn from Dr. Peterson. Bringing expertise and research to patient care is Simmaron’s mission.

Support the Simmaron Research Foundation’s Work to Scientifically Redefine ME/CFS

SR_match_10.9

__________________________________

“Immunology Primer for Practitioners” Panelists

  • Daniel Peterson, M.D., Owner, Sierra Internal Medicine, Incline Village, NV, Simmaron Research Scientific Advisor
  • Sonya Marshall – Gradisnik, BSc (Hons), Ph.D. , Professor of Immunology, Director, National Centre for Neuroimmunology & Emerging Diseases, Griffith University, Australia
  • Sharni Hardcastle, Ph.D., Research Assistant and Practical Demonstrator , Bond University, Gold Coast, Australia
  • Nancy Klimas, M.D. Ph.D., Professor of Medicine and Director, NSU COM Institute for Neuro-Immune Medicine Director, Miami VAMC Gulf War Illness and ME/CFS Research Program
  • Paula Waziry, Ph.D, Assistant Professor, Neuro Immune Medicine, COM, Nova Southeastern University, Miami, Fl
  • Konstance Knox, Ph.D., Founder, CEO, Coppe Healthcare Solutions
  • David Baewer, M.D. Ph.DMedical Director, Coppe Healthcare Solutions
  • Isabel Barao, Ph.D., Research Assistant Professor, University of Nevada, Reno, Simmaron Research Scientific
  • Gunnar Gottschalk, B.S., Simmaron Research, Incline Village, NV
  • Troy Querec, Ph.D., Associate Service Fellow, Centers for Disease Control and Prevention, Atlanta, GA
  • Dennis Mangan, Ph.D., Former Chair, Trans-NIH ME/CFS Research Working Group, Office of Research on Women’s Health, U.S. National Institutes of Health
  • Mary Ann Fletcher, Ph.D., University of Miami Miller School of Medicine Professor of Medicine, Microbiology/Immunology and Psychology
  • Elizabeth Unger, M.D. Ph.D., Chief, Chronic Viral Disease Branch, Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases. Centers for Disease Control and Prevention, Atlanta, GA

 

 

 

The Simmaron ME/CFS Physicians Roundtable Pt. II: Talking Treatments

Round-Table

meeting of the minds picture

Some of the top ME/CFS practitioners had a meeting of the minds on how best to treat ME/CFS at the Simmaron Roundable

Simmaron Research likes to get people talking. At the FDA Workshop earlier this year, they booked a room, invited patients and physicians and then held a physicians round-table with some of the field’s top doctors.

Part II of a three-part series focuses on Dr. Peterson of Sierra Internal Medicine /Simmaron Research Institute, Dr. Klimas  – the director of the Center for Neuroimmune Studies at Nova Southeastern University, and Dr. Enlander, the Director of the Mt. Sinai ME/CFS Research Center talking about chronic fatigue syndrome treatment.

Dr. Peterson – Simmaron Research Institute

Dr. Peterson started off the treatment section with some hopeful news. Powerful new immune drugs such as immune modulators and cytokine blockers), he said, that have been and are being developed, can have dramatic effects in the right patients.

upward slope

Immune therapies under development in other fields may be able to help ME/CFS patients in the future.

(Rituximab is an example of a new approach that paid off. The first of its class of drugs (monoclonal antibodies), Rituximab (Rituxan) opened up a new arena of drug development. Similarly, Ampligen and other Toll-like receptor affecting drugs offer new approaches to immune modulation. Drug repurposing efforts that are finding new uses for old drugs present some intriguing possibilities. An abortifacent, mifepristone, for instance, boosts natural killer cell functioning.

Breakthroughs in other fields are providing other opportunities. Studies documenting the role natural killer (NK) cells and the innate immune system play in preventing cancer have piqued drug developers interest enough the  several NK cell boosting drugs are in development.

A Treatment Philosophy

Some ME/CFS patients, believe it or not, are relatively easy to treat. Patients with easily characterized viral infections have a clear treatment protocol waiting for them. If a parvovirus infection is found, for instance, it can be easily treated. Dr. Peterson has found that the ‘wait and see’ approach so often prescribed by doctors with ME/CFS in hopes that the patient will just get better is a mistake.  He’s found that, in his group of patients, treating aggressively early is more effective.

cascade effect

Dr. Peterson proposes more aggressive approaches to ME/CFS early may forestall problems later if the disorder progresses.

(This brings to mind the story of someone I know whose doctor used a less strong antiviral (Valtrex) for a significant period of time only to switch to a stronger but potentially more toxic antiviral (Valcyte) after his patient deteriorated significantly. The patient then experienced a dramatic and lasting recovery.)

We’ll see that fighting pathogens in ME/CFS is not a cut-and-dried, one-size-fits-all process, and that physicians differ somewhat in their approach. In more complicated cases, for instance, Dr. Peterson is experimenting with combining immune and anti-viral treatments, and thus far is getting some encouraging results.

Dr. Peterson’s use of the antiviral Cidofovir (typically used to fight eye infections caused by cytomegalovirus in AIDS patients) demonstrates how differently even this small group of physicians sometimes approaches infections.

Cidofovir (Vistide)

“Cidofovir is not a panacea for this disease, but I think it demonstrates clearly how we should be subsetting and treating the treatable people,” Dr. Peterson.

Dr. Peterson uses Cidofovir regularly in patients with documented HHV6 and cytomegalovirus (CMV) infections.  (Since he employs more spinal taps than the other doctors at the Roundtable, he probably also finds more HHV6/CMV infections.)

Gunnar Gotschalk

Gunnar Gotschalk, Dr. Peterson’s research assistant, reported on Vistide’s results in ME/CFS patients with HHV6/HMV infections

Gunnar Gottschalk, Dr. Peterson’s research assistant, gave an overview of  the Vistide results seen in Dr. Peterson’s practice. Vistide is an expensive drug with potentially serious side effects that requires a rather complex infusion process.  Most patients need to relocate to the Reno/Lake Tahoe area to get at least 12 infusions.  Once they start the infusions they need to get three blood tests a week.  Vistide is difficult to administer, and its no surprise that most ME/CFS docs are not using it.

Gunnar reported, however, that a retrospective analysis indicated that 70% of ME/CFS patients with HHV6/CMV infections achieved a positive response.  He highlighted three patients: two achieved substantial gains in VO2 max and their viral titers dropped to zero, and all three returned to work after being disabled.

The retrospective analysis indicated significant drops in viral titers, increases in VO2 max (but not to normal) in full responders, and increased NK cell functioning in the group as a whole. Of the full responders Gunnar estimated two-thirds were able to maintain their health and one-third had to restart the treatment after 6-8 months.

When asked to compare Valcyte’s side effects with Vistides, Gunnar said that his experience was that people appeared to have a harder time on Valcyte than Vistide.

CMX001

Then there’s CMX001, the lipid-based analogue of Cidofovir produced by Chimerix that appears to be both more potent and better tolerated and which is beginning phase III (final) trials.

herpesviruses

If CMX001 passes muster at the FDA it will present new possibilities for herpesvirus treatment in ME/CFS

Simmaron believes it has patients that will fit Chimerix’s criteria and is trying to get them into the trials.  (Chimerix, by the way, generated $118 million dollars in gross proceeds when it went public a couple of months ago. Chimerix projects Phase III trials for CMX001 treatment of CMV infections in stem cell transplant patients will be finished in 2015. Since the drug is on fast-track status, the FDA will rule on it more quickly than usual once the data is in). Exactly what Vistide is doing (besides knocking down the virus) is unclear.

On the immune end, it’s possible Vistide is relieving pathogen-associated NK cell dysfunction (although Dr. Peterson thinks more than that is going on) but it’s unclear why the VO2 max readings in his patients go up.  Gunnar did allude to the fact that some deconditioning probably was present in these very disabled patients, but Dr. Peterson thinks cytokine induced mitochondrial dysfunction may be occurring.

HHV6 and Chromosomal Integration

The tricky problem of HHV6 chromosomal integration should be noted. People who have HHV6 integrated into their chromosomes will always, whether the virus is active or not, test positive for HHV6 via PCR. Retrospective studies are never proof of a drug’s effectiveness; you need a placebo-controlled, double-blinded study for that. But retrospective studies do provide the pilot data that could support a trial. (I was told that Dr. Peterson’s Paris presentation generated a lot of interest.) This retrospective study is an instance of a doctor combing through and analyzing their past data, and hopefully we’ll see more of it in the future.

Graded Exercise and Cognitive Behavioral Therapy

“I wish graded exercise and cognitive behavioral therapy worked,”said Dr. Peterson. After mentioning the CDC toolkit (which emphasizes CBT and GET and does not suggest ANY laboratory testing be done) Dr. Peterson said he wished CBT/GET worked, and then said it might be helpful for patients who’ve gotten well enough, but that even if it was, it’s simply not available. For all the talk on CBT and GET, Dr. Peterson knew of no trained practitioners in the US, except for one associated with Dr. Klimas’ clinic.

Dr. Nancy Klimas – Director of the Center for Neuroimmune Studies at Nova Southeastern University

“I’m a splitter not a lumper. I try very hard to find …intervention points,” Dr. Klimas

An  Autonomic Nervous System Focus

Earlier this year Dr. Klimas reported that gene expression tests done during and after exercise suggested that the autonomic nervous system ‘tanks’ first in ME/CFS during exercises, and then drags down the immune system with it.  Her research suggests autonomic nervous system problems trigger an ‘inflammatory cascade’ which then causes much of the post-exertional malaise that occurs in this disorder.

autonomic nervous system

Dr. Klimas exercise studies suggest the problems in the autonomic nervous system trigger problems in the immune system

It was no surprise, then, to hear her say that she spends a great deal of time early on with her patients trying to get that ‘volatile’ autonomic nervous system under control.  (This is an example of translational medicine; i.e., translating research results (gene expression findings) into practical applications in the clinic.) This ANS-immune cascade problem, by the way, appears to be independent of pathogen or antibody results; it’s a core issue present in many patients.

Pathogens and Immune Modulation

With regard to pathogens, Dr. Klimas said most of her patients with high antiviral loads/antibodies will be on antivirals, but generally more gentle ones such as Famvir (famciclovir). She noted, though, that a danger lurks when less-strong drugs inadequately control the virus: it can then ‘break free’ and develop resistance not just to that drug but to others in its class.  A virus that develops resistance to Famvir, for instance, will probably also be resistant to Valcyte. Dr. Klimas then made a plug for controlled clinical trials of Vistide in ME/CFS.

“We don’t really know how to distinguish which group is autoimmune and which group has chronic viral activation”

One has the feeling that the only thing keeping Dr. Klimas, an immunologist, from tinkering more with the immune system in her patients was lack of sufficient data. Referring to the weird immune ying/yang often seen in ME/CFS (some parts of the immune system being over-activated and some parts under-activated), she said she’d love to be able to knock down the immune activation present and build up immune cell functioning, but that building up cell functioning in a patient whose immune system is already overcharged could trigger an autoimmune response. Since no autoantibodies have been associated with ME/CFS, it’s difficult to tell if an autoimmune response is already present.

Some indirect tests can help; high CD4/CD8 ratios, for instance, are suggestive of autoimmunity, and high CD8 levels suggest a pathogen is present. If her flow cytometry tests show high CD4/CD8 ratios, she’s ‘very nervous’ about doing anything to bump up the immune system.

Immunovir (Isoprinosine)

Isoprinosine structure

Dr.; Klimas has had good success with Isoprinosine in ME/CFS

Dr. Klimashas seen an 85% response rate to Immunovir biologically, and it can generally double up NK cell functioning. She obtains pharmaceutical grade Immunovir from Canada Newport Pharmaceuticals and a similar and cheaper over-the-counter preparation called Inosine is available in the US.  Anecdotally she doesn’t think she’s getting as good a response from Inosine. Equilibriant – includes mushroom extracts that enhanced NK function in Chinese studies. Got lots of stuff in there.

Monoclonal Antibodies

A group of patients with extraordinary immune readings; i.e., TNF-a levels hundreds of times above normal, are prime targets for monoclonal antibody drugs (such as Etanercept) that target specific immune factors. In these patients, Dr. Klimas usually brings in a rheumatologist to get the drug.

Expect more news on this in the future, as a great number of monoclonal antibodies coming out of cancer research should be hitting the market, some of which may be able to assist NK functioning. Dr. Klimas said there’s “Some pretty cool stuff in the pipeline”.

“I want to make a plug for Low Dose Naltrexone” Dr. Klimas

Low Dose Naltrexone

Low Dose Naltrexone (LDN), not Lyrica or Cymbalta, is Dr. Klimas’ first line treatment for fibromyalgia-type pain.  A recent study found that it reduced FM pain by roughly 60% without the toxicity of Lyrica and Cymbalta.  She called the science behind LDN (which is not produced in a low-dose form by drug companies but is readily available at compounding pharmacies) ‘riveting’. That’s pretty strong endorsement of an ‘underground drug’ that is getting more and more attention despite its Achilles heel of not being marketed in low-dose form by Big Pharma.

Dr. Enlander – Mt Sinai ME/CFS Research Center 

GcMAF

Dr.  Peterson asked about GcMAF. Dr. Klimas said she hasn’t used it, but Dr. Enlander’s been using it for two years–first by injection and now mostly in his own yogurt mixture. Dr. Cheney probably may have started the GcMAF saga in ME/CFS first with a trip to Italy several years.  A yogurt mix was available, but when one of Dr. Enlander’s patients tried to make it the cost was  $3,000. In the end, Dr. Enlander’s bacteriologists at Mt. Sinai produced the mixture (MAF878) (and at a cost of $120!). Dr. Enlander does believe the injections are probably more effective, but he’s gotten good results for both.

Next Up: the Future! Dr. Peterson started off with hope, and in the next section we take a look at the future for ME/CFS physicians, what their three organizations are pursuing, and what they’re looking forward to in the future.

ME/CFS Physicians Roundtable I: ME/CFS Docs Talk Diagnostics and More at the Simmaron Foundation Roundtable

June 18, 2013

Listen in on the field’s top experts at your own pace here!

(Thanks to Anita Patton for her notes from the Roundtable talk)

FDA-Stakeholders-MeetingSimmaron likes to get people talking.  At just about every conference I’ve been to recently, the Simmaron Foundation has rented a room, brought in some food and got patients, doctors and researchers talking.  This time at the FDA Stakeholder’s Meeting they pitched Dr. Peterson, Dr. Klimas, Dr. Lapp and Dr. Enlander questions around a physician roundtable and took questions from the patients present.  We learned a lot in the off-the-cuff wide-ranging discussion that followed.  In this blog we’re going to look at how these doctors diagnose their patients and next up we’ll look at treatment.

Redefining ME/CFS

PetersonPhoto right

“We are on the verge of better diagnostics.” Dr. Peterson

Diagnostics always come first. Before you can treat you must be able to diagnose. Unfortunately the diagnostics in chronic fatigue syndrome have been shrouded, vague, symptom-based definitions. From the myalgic encephalomyelitis to the Holmes to the Fukuda to the Canadian Consensus Criteria,  the chronic fatigue syndrome field has been grasping for definitions for as long as it’s been around.

Problems on the macro level (the definition), of course, lead to problems at the micro level ( the doctor’s office) where  ME/CFS doctors are deluged with all different kinds of ‘chronic fatigue syndrome’ patients. That uncertainty – not knowing just who might step in the door –surely makes for an interesting job.  The qualifications for a good chronic fatigue syndrome physician may look something like this…. good listener, not daunted by complexity, loves to problem-solve, has a wide range of knowledge and is flexible and  willing to try new things…

As Bernard Munos pointed out at the FDA Workshop, in a disorder like this which has few clinical trials, the physicians, more than anyone else are the innovators. Not able to rely on clinical trials, their offices are an ongoing clinical trial.

How Dr. Peterson, Dr. Klimas and Dr. Enlander made sense of their ME/CFS patients was what the first part of the Simmaron Foundation’s Physician Roundtable was all about.  Listening to how the different doctors approached ME/CFS was fascinating.

“I am very concerned about random drug trials that take the first 100 patients who sign up.  It would be a disaster.” Dr. Peterson

Given the many different types of patients Dr. Peterson sees, the idea of drug trials that don’t subset first is simply appalling. The idea that this complex mix of patients are ever going to respond similarly to a drug is nonsense.

For Dr. Peterson, who sees the complexity of the illness daily, diagnosis, whether in a research study, clinical trial or a doctor’s office, always comes first. Since the same symptoms can be produced by many different factors, symptom definitions, while helpful, will always have flaws. What’s needed is to ‘scientifically redefine ME/CFS’; that’s the Simmaron Foundation’s stated goal and each of these physician/researchers is working towards that.

Now onto diagnosing ME/CFS.

Immune System

Dr Enlander

“Like Dan and Nancy, we look at the patient as an immune system problem in order to develop idea of diagnosis.”  Dr. Derek Enlander

Dr. Peterson started off by stating that after screening for the ‘obvious stuff’ he goes after immune markers, primarily focusing on the NK, T and B cells.

Over time he found consistent patterns began to emerge with natural killer (NK) cells playing a major role. (These cells, which play a major role in the early, innate immune response, appear to be ground zero for the immune problems in ME/CFS.  Unfortunately, they’re not particularly well known in the medical community.  Dr. Peterson’s poll of his colleagues in his area a couple of years ago found that few knew anything about them.)

It doesn’t help that natural killer cells are tricky to work with and need to be assessed within four-six hours of sample collection. In an attempt to make them more user friendly, Dr. Peterson is experimenting with freezing live cells in liquid nitrogen.Nancy Klimas

“We are the Gold Standard” Dr. Klimas

Being an immunologist it wasn’t surprising to see Dr. Klimas’s strong focus on the immune system. With one of the top immune labs in the country, Dr. Klimas is at the center of a lot of immune work.

Immune factors are one lab measure you’ve got to get right; tweak the powerful immune system the wrong way and you can cause a lot of trouble. If you’re  using immune altering drugs, and both Dr. Peterson and Dr. Klimas do, the ability to trust your lab is critical. Dr. Klimas said her immune lab is the ‘gold standard’ and Dr. Peterson gets all his cytokine arrays done at Dr. Klimas’s lab.

Dr. Klimas will dig into IGG subclasses if she sees bacterial infections. Dr. Enlander focused on much the same factors;  CD4 and 8 ratios, NK cells and function, (IL2, IL4, IL10) and uses bacterial cultures to rule out other disease entities, like Lyme, etc.

Pathogens

Pathogens were discussed briefly. All three physicians were testing for them (eg; EBV, HHV6, CMV, Parvovirus, Coxsackie and bacteria)  but there were some differences. Dr Enlander did not see a relationship between viral load and disease severity, something that Dr. Peterson, as we’ll see later has found, at least with one group of patients. Dr. Klimas has not found HHV6 to be a good marker either as patients don’t test positive consistently; in fact, she called ME/CFS a ‘good day, bad day viral disease’ as patients may test negative on a good day and positive on a bad one. That’s helpful for her as a physician but is not good enough for the FDA to test treatments against. The FDA needs a test that’s consistently positive.

InfectionsWhat does Dr. Klimas find that tracks with severity?  Natural killer cell functioning and IL-5 levels  might be two markers the FDA could use to assess treatment effectiveness.

We don’t hear alot about IL-5 cells but they boost two immune factors of interest in ME/CFS; mast cells and B-cells.  Overactive B-cells cause autoimmune disorders and, of course, also  harbor EBV as well.

Dr. Enlander will be seeking to confirm/deny Dr. Chia’s enterovirus findings in his exercise study (see below.)

Autonomic Nervous System

With Dr. Peterson stating the amount of autonomic nervous system dysfunction in ME/CFS was ‘huge’ the stage was set  for the autonomic discussion. All three doctors do blood pressure and pulse testing with Dr. Peterson and Dr. Enlander doing 24-hour BP and heart testing, and Dr. Enlander and Dr. Klimas use tilt table testing. Dr. Klimas noted that an autonomic nervous system dysfunction appears to trigger immune dysfunction. She asserted that the sympathetic nervous system a major, major symptom generator in this disorder and she rattled off problems with standing, respiration, poor digestion, etc. that could all be caused by SNS overactivation.

Nervous-SystemIt’s not clear how many of the physicians were measuring blood volume; it may be that they all simply assume blood volume is low, but Dr. Klimas noted the astounding fact that most patients are about a liter of blood low, or about 20% down from normal. With that little blood running through your blood vessels those blood vessels are going to have to squeeze hard  to get it out to the tissues and brain, and right there you have a good reason for the sympathetic nervous system activation Dr. Klimas talked about earlier.

Dr. Klimas gives blood volume a boost with electrolytes and then puts the patients back on the tilt table to see if they’ve improved.

Dr. Enlander is using Dr. Cheney’s cardiac protocols to measure cardiac output, stroke volume, etc. He does it, interestingly enough in a variety of positions (lying down, standing) giving him a great deal of data on cardiovascular functioning.

With the ANS playing a huge role in exercise, onto to exercise testing we go.

Aerobic Testing

“You do better diagnostics when you do exercise challenges.” Dr.Nancy Klimas.

You probably couldn’t get three ME/CFS physicians more knowledgeable or committed to exercise testing in one room than you had at the Roundtable.

The first ME/CFS physician to embrace VO2 max testing, Dr. Peterson made a strong plug for Staci Steven’s test-retest, two day exercise protocol (the Stevens Protocol. This exercise test grew out of the work she did in Dr. Peterson’s office).

Dr. Peterson uses the most rigorous test of all; the aerobic exercise test to determine how well his interventions are working.   At the FDA Ampligen hearing, Dr. Bateman, noted that the VO2 max test, which measures the amount of energy a person can produce, is the hardest to budge of all ME/CFS tests . Since Dr. Peterson finds that low VO2 max scores are often correlated with poor cognition, abnormalities on MRI’s and spinal fluid as well as autonomic problems, bumping up those VO2 max scores even moderately can mean a significant improvement in functionality and well-being.

Exercise-test-cfs

All three practitioners use exercise testing in for research, disability and/or to assess the effectiveness of their interventions

( I asked Staci Stevens if she knew of any  ME/CFS patients who had returned to full VO2 max functioning and she said yes, some patients on antivirals and Ampligen –coming out of, no doubt given her longstanding connection with him, Dr. Peterson’s office.)

Dr. Klimas has been digging deep into exercise in her research, lately, which, in turn is informing her diagnostic work.  (That’s  ‘translational medicine’).  Earlier this year she reported gene expression studies indicated that the autonomic nervous system tanks first during exercise and then drags the immune system down with it.

This major finding, if validated, suggests breakdowns in the ANS, which is ever so tightly intertwined with the immune system, could be at the core of the disorder.

“Now let me tell you what we are really doing at Mt Sinai…” Dr. Enlander

And then there was Dr. Enlander who’s committing  a big chunk of money to a sophisticated exercise testing study at the Mt Sinai Research Center. He’s got a geneticist, an immunologist and a pulmonologist all working together.

After exercise Enlander’s team will be looking at RNA (genes), blood (immune factors, a stool sample, RNA, DNA genome, enteroviruses), brain MRI and SPECT scan. Amongst other things Enlander will be looking to confirm or deny Dr. Chia’s findings of enteroviruse of seven, yes, seven years ago. That’s seven years without a confirmatory study of a virus that was first linked to ME/CFS decades ago…

Spinal Taps and Brain Imaging

Dr. Peterson does spinal taps  to figure out what’s going on with his most cognitively challenged and neurologically impaired patients. (After decades of gathering spinal fluid, Dr. Peterson easily has the greatest store of ME/CFS spinal fluid on the planet. Dr. Mady Hornig has referred to Dr.Peterson’s spinal fluid as a precious resource).

spinal fluid

Dr. Peterson examines the spinal fluid of his more neurologically and cognitively challenged patients

Spinal taps are where Dr. Peterson, Dr. Klimas and Dr. Enlander part ways to some extent. Both Klimas and Enlander do them at times, but Dr. Peterson does them routinely in patients with neurological and brain issues (and he does them himself).  Dr. Klimas said she was astounded that Dr. Peterson found 17% of his patients’ spinal fluid tested positive for a virus.

Both Drs. Klimas and Enlander may be doing them more in the future. Dr. Klimas is waiting on finding the right neurologist, and Dr. Enlander said he was closely following Peterson’s ideas.  If the CFI and PHANU studies using Dr. Peterson’s spinal fluid are positive, we may see more and more doctors turning to spinal fluid to assist with their diagnoses.

Future -Dr. Peterson looked forward to future medical advances that will help him fine-tune his diagnostic protocols.  Genetic technologies are indicating, for instance, that a genetic predisposition to the NK dysfunction may be present in ME/CFS. On the other hand he also finds ‘acquired’ (ie non-genetic) NK cell dysfunction as well. He believes insights gathered from miRNA’s in the spinal fluid of ME/CFS patients, for instance, and the more rigorous pathogen detection techniques will continue to open up this field and inform his diagnostics.

Similarly, Dr. Klimas’ exercise studies are causing her to focus more on improving autonomic dysfunction, and Dr. Enlander will use his big exercise study to inform his understand of his patients. Each of these three physician/researchers is eager to translate their research findings into their diagnostic protocols.

Undefining ME/CFS?

“There is an entire school of thought in the medical profession that if anyone with chronic fatigue has anything objectively wrong with them – they don’t have chronic fatigue syndrome.” Dr. Dan Peterson

After all the talk about how to diagnose ME/CFS, Dr. Peterson brought up a trend towards ‘undefining’ that he found troubling. Undefining ME/CFS consists of putting ME/CFS patients in a different box as soon as something concrete is found.   Stating that this attitude is more forceful than he ever thought, Dr. Peterson explained that a person with ME/CFS with HHV6A in their spinal fluid will be labeled as having HHV6A encephalitis and be determined to never have had ME/CFS.

ME-CFSDr. Klimas acknowledged that while getting a diagnosis that can be treated is great, as a field winnowing large numbers of patients out of the ME/CFS basket could be devastating. For one it condemns ‘ME/CFS’ to be a  a mere placeholder of an illness.

Dr. Klimas noted Dr. Peterson’s finding that 17% of his cognitively dysfunctional patients were culture positive for viruses in their spinal fluid was a clear subset.  (She was reminded of former CDC CFS chief Bill Reeves response “you don’t know that doesn’t belong there” and she laughed and said “Wait a minute . Would it be ok for you to have your cognitively dysfunctional child culture have positive spinal fluid test? I don’t think so”). What a dilemma it was, she said when every time we start to get clarity, part of this disorder gets shuffled off into another column.

The Hidden Epidemic

“The bedridden patients – It’s the hidden epidemic within another epidemic..It’s scary” Dr. Dan Peterson

And then there’s the missing patients; the bed-ridden ones that rarely get to doctors clinics and certainly aren’t in research studies.  How do you define a disease without access to all the patients?  The most severely ill usually get the most attention in most disorders but the opposite is true in ME/CFS.  (Check out the astonishment from a former ICU nurse working with Dr. Kogelnik at the degree of disability she sees in ME/CFS. These patients, she thought, should be in a hospital, not at home.)

“Talk about a forgotten, ignored group of people.” Dr. Peterson

Dr. Peterson noted that we don’t an accurate count of how many people are in this situation. He didn’t have answers. He noted that you needed staff to get to these people and you needed to find them in the first place. Dr. Klimas answer suggested that funds were at the heart of the problem. Ads for an online CBT study did bring in bedbound patients who were unable to make it to the clinic and funding for the ‘good-day/bad-day’study did allow them to make house-calls on the patients bad days. Both Dr. Klimas and Dr. Enlander said they do do house-calls from time to time. (One of Dr. Enlanders house-calls is now up and working…he said there is hope for the severely ill.)

Listen to audio of the Roundtable in 7 parts here, and stay tuned for a blog summarizing the Roundtable discussion about treatments.

Infection, Autoimmunity and PANDA’s: Dr. Hornig on Chronic Fatigue Syndrome at Dr. Klimas’ NSU Conference

Quite the Resume

Dr Mady Hornig comes with quite a resume. She and Dr. Ian Lipkin MD direct the Center for Infection and Immunity at Columbia University in New York, and Dr. Hornig is directing the Pathogen Discovery and Pathogenesis Program at the Chronic Fatigue Initiative (CFI).

The Hornig/Lipkin lab at Columbia University is involved in numerous ME/CFS studies

The Hornig/Lipkin lab at Columbia University is involved in numerous ME/CFS studies

An MD and immunologist with a background in neuropsychiatry, Dr. Hornig’s been focused throughout her career on uncovering immune dysfunctions associated with mood and developmental disorders such as autism, PANDA’s, ADHD and schizophrenia. Her current work on the MIND (Microbiology and Immunology of Neuropsychiatric Disorders) Project constitutes the largest examination yet of the role the immune system and viruses play in mood disorders and schizophrenia. She’s currently a lead investigator for  the Autism Birth Cohort study determining how development, genes and environmental factors combine to produce autism.

Dr. Hornig has quickly become a major chronic fatigue syndrome investigator and said she and Dr. Ian Lipkin were using all the tools available to them including gene expression studies, immune and stress markers and proteomics using mass spectroscopy.Check out the ME/CFS studies her lab is or has been involved in….

Chronic Fatigue Syndrome Studies at Dr. Hornig’s Laboratory

  • 200/200 Cases and controls with Chronic Fatigue Initiative  – 18 pathogens identified, then unbiased high throughput sequencing – pretty much tell us anything that is in there
  • 150/150 cases/controls in XMRV study
  • 400/400 cases/controls in huge Montoya Stanford study
  • 60 cases/60 controls Simmaron Spinal Fluid Study

Dr. Hornig focused in on the Simmaron Institute spinal fluid study calling it ‘really intriguing’, calling the number of well-characterized spinal fluid samples  ‘unparalleled’, and stating the study was a ‘unique opportunity’.

We’ll get another chance to see her at the 2013 Invest In ME Conference in May.

The Talk – Infection, Autoimmunity and Illnesses

Placing chronic fatigue syndrome into the category of ‘neuropsychiatric disorders’ (disorders that effect cognition and mood among other things) Dr Hornig started off her talk demonstrating how attacks of insanity seem to have swept over populations, not suggesting that she’s studying a group of insane people, but demonstrating how infections can generate symptoms we don’t generally associate with them.

Mom???

Dr. Hornig believes three factors, timing – a window of opportunity,  a genetic predisposition, and an environmental insult probably come  together to cause chronic fatigue syndrome.  That window of vulnerability could have occurred at any time but Dr. Hornig zeroed in on pregnancy:  a time, it appears, when many chronic disorders are  set into motion.

Mom? The roots of some chronic illnesses appear as far back as pregnancy

Mom? The roots of some chronic illnesses appear as far back as pregnancy

She suggested, but did not say, that chronic fatigue syndrome could be triggered as early as pregnancy and then not show up for 20 or  40 or 50 years until  another window of vulnerability opens up – perhaps during a stressful period, another infection, toxic overexposure. (She noted that the stress response is similar in all these cases).   Indeed, that model of disease, she said,  could apply to outbreaks of autism and ADHD in early life, multiple sclerosis, schizophrenia and ME/CFS in middle life and Parkinson’s and Alzheimer’s disease in later life.

Cannabis triggered schizophrenia during adolescence is an example of the three factors combining in a perfect storm to cause a devastating  disease.  It turns out that bringing together one form of a COMT gene (the COMT gene, oddly enough is implicated in ME/CFS), the tumultuous physiological time of  adolescence, and an environmental factor (cannabis) you get an increased risk of (gulp) schizophrenia.  Basically smoking pot when you’re an adolescent increases your risk of  schizophrenia (it happened to one of the my best friends) but smoking it when you’re an adult – even if you have this particular form of this gene- doesn’t increase your risk at all.

She described an incredible and rather frightening study in which researchers examined pro-inflammatory cytokine levels (IL-6 and IL-1b) in the blood of mothers collected 40-50 years ago. Skipping  forward they found that women whose mothers had high cytokine levels during pregnancy  tended to be depressed and have reduced  brain activation in middle age. This suggested those high levels of pro-inflammatory cytokines changed the circuitry of female fetus’s brain enough to make those women more vulnerable to depression later on.  She noted that some of the same stress-circuitry showing up  in those women is implicated in ME/CFS as well.

The Immune Side of Neuopsychiatric Disorders

Hornig is an immunologist and she  explained that many ‘neuropsychiatric disorders’ may be explained by immune problems; the list  she presented was not a particularly pretty on; besides fibromyalgia and ME/CFS it included Tourette’s syndrome, autism, obsessive compulsive syndrome, ADHD, anorexia nervosa, narcolepsy, major depressive disorder, bipolor disorder and schizophrenia (and probably should have included irritable bowel syndrome, interstitial cystitis and other disorders that co-occur with ME/CFS. ).

There are several  groups in here; the heavy psychiatric disorders – depression, bi-polar disorder, compulsive obssessive disorder and schizophrenia; the CFS-like disorders (ME/CFS, FM….IBS, IC, etc.) and then autism and ADHD.

The Infection Autoimmune Connection

The infection/autoimmune connection is a strong one with many autoimmune disorders showing up shortly after infections…but..(there’s always a but :))  she noted that other autoimmune disorders  can take years to show up making it difficult to determine the trigger.  If it was a pathogen, it could’ve  and may very well have done it’s damage and then disappeared, leaving a chronically disrupted immune system in its wake.

PANDAS – A Possible  Model for ME/CFS

“Several studies suggest autoimmunity may play a role…”

PANDA's - a childhood disorder associated with Streptooccus infection could be a model for ME/CFS

PANDA’s – a childhood disorder associated with Streptooccus infection could be a model for ME/CFS

Hornig  then described an infection triggered neuropsychiatric disorder called PANDAS that could be a model for ME/CFS.  Children with PANDAS don’t eat eucalyptus leaves for lunch, but they do display dramatic changes in behavior including obsessive-compulsive behavior, tics, mood swings and anxiety soon after a staphyloccus infection. They also display the kind  of ‘ vigilance’ and arousal that shows up in some people with chronic fatigue syndrome.

Hornig has become deeply involved in PANDAS. Much is controversial about PANDAS but it’s believed to be an autoimmune disorder that targets the basal ganglia in the brain (which is, yes, also under consideration in ME/CFS…). Working with Dr. Lipkin, Dr. Hornig found that mice injected with strep   engage in obsessive compulsive behaviors (they flip themselves over backwards again and again) and that simply injecting  antibodies to streptococcus  into mice caused problems with learning and memory, coordination, and social interactions.  Then, in a nice Koch-like test, they found that  removing the antibodies from the mice  resulted in the return of  normal behavior.

General Stress Response Affected

That made it pretty clear  it’s the antibodies; eg. the immune response that’s the problem and what they found next confirmed that; they found that the antibodies to strep mistakenly cross-react (ie  target  for destruction) two important parts of  the  immune system; C4 complement and heat shock proteins.

Why would we, with ME/CFS, be interested in these factors?  Because both  appear, Dr. Hornig said, to be general responses to infections and stressors of all sorts, with all its different triggers, chronic fatigue syndrome could be associated with a basic derangement of the stress response (to  infection, trauma, etc.).

Dr. Hornig didn’t mention it both C4 and heat shock proteins  have (yes, yes, yes :)) been implicated in chronic fatigue syndrome at one time or the other

Dr Hornig noted that children with  PANDAS can respond to IVIG, antibiotics and other immune agents.  That’s a bit controversial (no surprise there) with  the American Heart Association (AHA)  recommending that strep not be tested for in children with PANDAS or that they attempt IVIG  treatment despite the fact that one preliminary  study has found IVIG effective.

It’s more of the old, we need more studies before we do or recommend anything without providing the money to do them leaving potential helpful treatments on the shelf while patients suffer (sound familiar?). (PANDAS is way down on the NIH’s priority list.

Key Partners – The Stress Hormone-Immune System Interactions

Hornig noted the immune- stress response connection with PANDAS and now she enlarged on it. Proper central nervous system functioning is dependent on having  balanced immune and stress responses; throw those responses in just one part of the system-  tryptophan degredation – into disarray can cause you to not be able to lay down a memory. Tryptophan is a possible candidate with ME/CFS but she was most interested in the biggest bundle of nerves outside the brain – the enteric nervous system or gut….

Getting Down With The Gut

Hornig then directed us out of the brain and downwards into the gut.  On a very, very basic level this makes sense since  everything  that our bodies run on (except for the gases) comes from our food which means we better be able to digest it well. Stopping the flow of anti-oxidants  (selenium, cysteine, glutathione) from our food out of the gut into our body, for instance, results in increased levels of oxidative stress,  pro-inflammatory cytokines and auto-antibodies  (autoimmune reactions).

Get increased auto-antibodies and you can have problems showing up in literally any part of the body. Just to get our attention, Dr. Hornig noted that an  autoantibody attack of folate receptors could show up in problems with  metabolism,  methylation and B-12.

Then she shifted upwards – back to the brain.  So far our dysfunctional gut has left us with low levels of anti-oxidants, high levels of pro-inflammatory cytokines,  and high levels of autoantibodies in our blood.  Send all that stuff up to the precious (and fragile) blood-brain barrier  protecting our brain and….you have the possibility of a rip exposing the brain to all sorts of bad actors. Depending on which part of your brain gets attacked there goes your  sex drive, appetite, motivation, energy levels, etc….and to think it all could have started with bad flora in your gut.

More Floral Than Viral?

Lest we think this is some researcher’s fantasy, Hornig described her work with autistic kids.  Hornig’s group did not find evidence of measles in autistic children but they did find levels of digestive enzymes so low to be almost non-existent. The autistic kids couldn’t break down milk products because they were lacking the enzyme for that but that hardly mattered as their guts were so deficient they couldn’t have gotten the milk protein into their bodies even they could have broken it down.

Not only was their gut flora massively different but they also they harbored a rare bacteria called Sutterella not present at all in the healthy controls.  Sutterella was not just present,  it was flourishing, accounting for up to  7% of all gut bacteria. Usually a very minor component of the gut microbiome, Suttarella was the third most common bacteria found in these kids.  That really raised some eyebrows.

Could ME/CFS be More Floral than Viral? An upcoming CAA study should be revealing. These bacteria were cultured from yogurt

Could ME/CFS be More Floral than Viral? An upcoming CAA study should be revealing. These bacteria were cultured from yogurt

Still, it’s not clear if Sutterella itself is whacking the kids or if its crowding out good gut flora or if its doing nothing but  we do know that Sutterella thrives in low oxygen  environments and has been linked to inflammatory bowel disorder, Crohn’s disease and ulcerative colitis. (It  can also, though, sometimes be found in healthy individuals.) Hornig’s ability to find an antibody to Sutterella in about 50% of the children indicated they had mounted an immune response to it.

Bacterial imbalances in the gut have been observed in gut disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease but its become clear that  bad gut bacteria could wreak havoc far outside the gut. The first non-gut disorder associated with bad bacteria appears to have been arthritis.  (Check out a horrifying and fascinating New York Times story of  young child’s battle with rheumatoid arthritis.)  Cesareans appear to  put children at increased risk for asthma because they prevent children from picking up important gut bacteria as they pass they through the birth canal.   Bacterial imbalances in the gut appear to be associated with increased obesity in people with  type two  diabetes .

Researchers have identified three main types of gut composition in humans and they know that diet can influence gut flora. They know that  cutting out sweets and processed foods and using prebiotics and probiotics can help some people reduce or eliminate  inflammation.  Fecal transplants may actually be more effective because they contain more of the bacteria that’s actually populating our guts.

Hornig noted how  important the small intestine is for so many different type of phenomena – for cognition, anxiety and even for sleep. Did you know that if you’re not getting peristalsis (small gut movements pushing the food along)  during the night then you’re missing some sleep enhancing molecules.

Major Chronic Fatigue Syndrome Gut Study Out This Year

The Shukla CFIDS Association gut metagenome study is looking more exciting all the time. This study, which study started several years ago and should be published soon, sought to characterize the entire  gut microbriome before and after exercise in people with ME/CFS.

By studying the gastrointestinal microbiome, Shukla’s work will determine if the ratio of normal to pathogenic (illness-causing) bacteria is off-kilter in CFS patients and if exercise causes harmful bacteria to travel into the body from the gut, creating the postexertional symptoms that are such a prominent feature of the illness. The results have the potential to yield microbial biomarkers for CFS as well as targeted treatments aimed at rebalancing the ratio of bacteria. From CFIDS Chronicle Winter 2009

  • Xafaxan: Gut Rebalancer Extraordinaire –  Suffering from gut issues? Check out a new page Health Rising has on Xafaxan, a gut antibiotic used to snuff out small intestine bacterial overgrowth (SIBO) problems. One person with ME/CFS ended six years of gut turmoil with one short course of Xafaxan…

 Q & A Period

Is Chronic Fatigue Syndrome Infectious?

She thought perhaps, but if so probably mostly during the initial stage of the illness, and that it was highly unlikely it was  infectious in later stages of the illness.  Hornig is following the same model as Klimas in her research; she’s  looking for an infectious agent but finding  immune and stress response factors indicative of a pathogenic attack (at some point) is a major focus.

With a kind of immune system hypervigilance twist she stated its possible an initial infection sensitized the system so that further infections, even very mild ones, might be  throwing it  into a tizzy.   If ME/CFS patients have a problem with infection in general; that is, if any infection has the potential to trigger a kind of overwrought immune response, then she felt it was more important the source of that than to look for a specific virus.  With all the known infectious triggers for ME/CFS she believes some genetic susceptibility/immune issue was present.

One reason for Hornig’s interest in ME/CFS may be due to her work in autism. Hornig believes innate immune system problems during maternity may play a role in the development of autism, and the innate immune system  – the early immune response system involving NK cells, dendritic cells and others – is getting more and more attention in ME/CFS.  Interestingly, Hornig found that infection induced inhibition of the same Toll-like receptors (TLR3) Ampligen effects lead problems with sensorimotor gating responses as adult.  Check out this blog for a treatment of sensory gating issues in chronic fatigue syndrome.

_________________________________________________________

Clin Invest Med. 2008 Dec 1;31(6):E319-27. Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndromepatients and matched healthy controls. Thambirajah AASleigh KStiver HGChow AW.

J Intern Med. 2009 Aug;266(2):196-206. doi: 10.1111/j.1365-2796.2009.02079.x. Epub 2009 May 19.Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses. Jammes YSteinberg JGDelliaux SBrégeon F.

Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins. Jammes Y, Steinberg JG, Delliaux S. J Intern Med. 2012 Jul;272(1):74-84. doi: 10.1111/j.1365-2796.2011.02488.x. Epub 2012 Jan 4.

Mol Psychiatry. 2010 Jul;15(7):712-26. doi: 10.1038/mp.2009.77. Epub 2009 Aug 11. Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Yaddanapudi K, Hornig M, Serge R, De Miranda J, Baghban A, Villar G, Lipkin WI.

J Allergy Clin Immunol. 2003 Aug;112(2):397-403. Complement activation in a model of chronic fatigue syndrome. Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, Jones JF.

Mol Med. 2009 Jan-Feb;15(1-2):34-42. doi: 10.2119/molmed.2008.00098. Epub 2008 Nov 10. Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome. Sorensen B, Jones JF, Vernon SD, Rajeevan MS.

Great Start – Big Plans Ahead: Dr. Klimas at her NSU Coming Out Party

Dr. Klimas has big plans for her new Institute on Neuroimmune Research at NSU

Dr. Klimas has big plans for the new Institute on Neuroimmune Research at NSU

A Coming Out Party

The coming out party for Dr. Klimas Institute for Neuroimmune Research at Nova Southeastern University (NSU) on January 26th was a year in the making.   In 2011 NSU had made her an offer she couldn’t refuse –  the opportunity to break down what she called the  silo’s that separated researchers, clinicians and educators  – and in  Dec 2011 she announced, after decades or work at the University of Miami, she was leaving to  create a new Institute at NSU.

In the Institute’s first public event, a  Patient Conference,  she brought together members of the Institute to talk about it. After the Dean’s short introduction, Dr. Klimas  gave the first presentation.

The Big Plan : Finding Effective Therapies

 (Warning…I frequently take riff’s on  the presentations (see Waziry and EBV below) ; if something in these blogs turns out to be incorrect, it’s probably due to  my riff :))

Dr. Klimas’  presentation was titled a BIG PLAN and it’s a plan  that is  focused towards one goal…”Finding Effective Therapies”. Dr. Klimas’ effort is fundamentally oriented towards finding effective therapies and we’ll see how that’s going to work in a later presentation.

The mission statement pointed out just what kind of disorder Dr. Klimas believes chronic fatigue syndrome is…a “neuro-inflammatory” disorder; a nervous system disorder involving inflammation; ie  immune activation.

Dr. Klimas emphasized that the reason she came to NSU was to create an integrated program that has the  clinicians, researchers and educators  all working together in a tightly knit group.  Each person, she said is  engaged in all of it; the doctors are talking with the researchers who are informing the educators.  In fact the way the building is structured they have to communicate; everyone eats and meets in the same central meeting/ conference room.

The Institute focuses on two groups, people with chronic fatigue syndrome and people with Gulf War Illness (GWI)

Gulf War Illness (GWI)

Introducing Gulf War Illness Dr. Klimas stated the  remarkable fact that fully 1/4 of the Gulf War Vets (that’s 200,000 people and some estimates are higher)  returned with a chronic, often disabling multisystem illness ….(sounds like ME/CFS?)…that looks like ME/CFS but is biologically very  different.  What happened? It appears that a  toxic cloud of elements from gas fires, pesticides, vaccines, uranium etc.  with the major contributor probably being something we’ve all been exposed to at times;  pesticides.

  • Dig Deeper: Check out a  recent fascinating New York Times article  suggesting that contaminated dust and  Sarin, a close cousin of organophosphate pesticides, were  key factors in GWI.

That toxic insult is probably long, long gone but that initial insult  appears to have reset many GW participants systems permanently and Dr. Klimas is trying to figure out how to reset  the reset button.

Chronic Fatigue Syndrome (ME/CFS)

Dr. Klimas’s test results suggest an insult is still present in ME/CFS. (More on that later). Calling it a terrible illness Dr. Klimas noted that 1/4 or more of people with ME/CFS are fully disabled and many more are partially disabled and that the disease with the funny name is as debilitating  as heart disease, end stage kidney disease, AIDS (AIDS !!!) and MS.

She laughed at one idea she  come across at times; that people with ME/CFS  want to be on disability and the poverty level income that provides them instead of having access to their income they enjoyed previously; yes, she laughed , what a great tradeoff that would be.

The People

Dr Waziry will focus on determining what pathogens are doing to the cells of people with chronic fatigue syndrome

Dr Waziry will focus on determining what pathogens are doing to the cells of people with chronic fatigue syndrome

Thus  far the Institute has on board researchers specializing in  gene expression (Nathanson),  viral effects (Waziry), clinical research (Dr. Klimas) and two computational biologists,  (Broderick and Cradock) and, I’ve been told, may be adding an animal modeler.

Pathogens

Waziry specializes in a key, key area – detecting how  viruses muck up how cells operate. If  viruses are present you, of course,  want to get at them but if the viruses are gone or are hard to find  then finding some sort of viral fingerprint could inform you how the damage occurred, where to target treatments and  what viruses to look for would be very helpful and that’s what Waziry is doing.

Given the common infectious trigger in this disorder  this slant makes  sense; something, after all, happened way back when and for many people it involved a pathogen.  If  Waziry finds a signature unique to cells that  Epstein Barr Virus mutilated, for instance,  you’d know your pathogen without having to resort to expensive and not always accurate blood tests.  It’s also possible, given the many  infectious triggers documented in ME/CFS (EBV, parvovirus, coxsackie, West Nile Virus, Giardia, etc.) that they’re all tweaking the system in the same way.  If that’s what’s happening then  finding a common immune signature will allow the team to develop simple diagnostic tests for a significant portion of ME/CFS patients.

Computational Biology

The computational biologists are trying to stop the illness cascade in its tracks in chronic fatigue syndrome

The computational biologists are trying to stop the illness cascade in its tracks in chronic fatigue syndrome

Dr. Klimas has fully  embraced a new branch of  biology called computational biology that uses sophisticated data mining techniques to analyze  how our internal  systems operate.  In fact Dr. Klimas has so fully embraced this type of research that her computational biologists are doing cutting edge work not being done in any other disease.

The computational biologists (Broderick and Crawford) play clean up. Every piece of  research and clinical data gathering ultimately ends up in their hands. They’re trying to do something unique in medicine;  using data mining techniques to target the molecular source of this disease in time.  Think of it as isolating the pebble the started the snow slide that ended creating an avalanche.  This isn’t about symptom amelioration anymore; this is about getting at the very beginnings of the system-wide ‘collapse’ that occurred and is still occurring  in people with ME/CFS.

The computational biologist are the ones, Dr. Klimas explained, that will ultimately be able to tell her that  tweaking this  patients HPA axis here, and prodding their  immune system over here and here,  should stop the cascade of system-wide dysfunction that  causes chronic fatigue syndrome…Essentially she wants to cut a relapse or flare  off at it’s …er…..start.

We’ll learn more about this approach in Broderick’s talk.

Speeding Up the Process

Dr. Klimas wants to move quickly. No more of this  waiting two years for the NIH to respond;  Dr. Klimas – through a process Dr. Broderick will outline later – hopes to produce multiple small-scale, phase-1 type clinical trials in house to get the  data needed to get pharmaceutical companies interested in drugs that will help ME/CFS patients.

The Institute

At this point the Neuro-immune Institute has  11 staff members including 6 researchers/research assistants, a research coordinator, a Director of Medical Education, two Nurse Practitioners (one of whom has ME/CFS) plus researchers from the University of Miami, University of Alberta, Wright State,  and the CDC . And they’re busy with no less than seven different active studies going on at the moment.

Accomplishments of the Past Year

Dr. Klimas announced two encouraging signs; (a)  they’d achieved more in the past year than expected and (b) Nova kicked in more than she expected.

In the first year the Institute for Neuroimmune Research has been involved in

Research

  • a really large DOD grant
  • Genomic studies
  • Gene expression and immune regulation study
  • Gene expression exercise study
  • GWI animal modeling
  • CDC – multisite ME/CFS physician study
  • Chronic Fatigue Initiative Pathogen Study – Dr. Klimas stated that the CFI, which  is the most well-endowed ME/CFS research foundation,  is motivated to come up with answers quickly as well, and that the pathogen samples in the big Lipkin/Hornig study are being analyzed now. She stated the Institute would  continue their work with CFI, suggesting that further studies are around the corner.
  • Epidemiological Study – stating this has never been done before, this study has tracked people back as far as  10 years and asked them how they’re doing now; thus far 1,000 people have answered the questionnaire. Smiling broadly she said they did it on student stipends; $8,000 (a site?) – a ridiculously low figure  – and they’re getting important, never before seen data.
  • Ampligen Study

Treatment

  • Doubled the clinical space at their  Kendall clinic
  • Created a  new clinic at Davie

An Effective Team – Dr. Klimas mentioned how effective she and  Mary Fletcher, whom, she said does not sleep and works weekends (we’ll see evidence of that later :)), were at writing and getting NIH grants. That’s very true; while other ME/CFS researchers have given up on the NIH and few get grants, these two always seem to be in the mix at the NIH.   Their ability to consistently get grants for this  disorder is extraoardinary and is partially because of the interest in the cutting-edge computational biology approach they’ve taking.

Goals for this Year

Next Dr. Klimas went over their goals for this year.

We’re going to be able to collect huge mountains of data on normal care and make the evidence happen….Dr. Nancy Klimas

 Turn the Clinical Database into A Research Database (and then analyze the heck out of it)

The plan, is to integrate her clinical databases into her REDCAP  research database, providing her sophisticated  tools to analyze treatment effectiveness in her patients, past and present. If you’re part of her clinic (with your permission) you’ll become a research partner as well.

Integrating her clinical database into her research database could allow Dr. Klimas to answer many question about treatment effectiveness

Integrating her clinical database into her research database could allow Dr. Klimas to answer many question about treatment effectiveness

This is big stuff. By putting her patients into  a research database made for, well, research and analysis – Dr. Klimas is opening up thousands of records and patient outcomes to  analysis. Over time this will bring  treatment outcomes  out of the fog of individual guesswork and intuition into the clarity of statistically derived analysis.  No more waiting for for someone spend two years convincing the NIH to fund a small treatment trial….those trials have effectively been underway in ME/CFS specialists offices for decades; they’re just waiting to be uncovered.

Doxepin elixir is commonly used to aid sleep in chronic fatigue syndrome but how effective is it really? Are there certainly types of patients it works better in?   Would some patients do better with Ambien? Nobody really knows the answers to these questions but given the staff and funding  they are answerable with this technology.

If this really works, this work, and Dr. Kogelnik at the Open Medicine Institute has similar plans, would be a bonanza for both patients and doctors. Since the CDC doesn’t seem to be able to handle non evidence-based data, we could anticipate an entirely new CDC Toolkit, for example, coming out of  this work.  Dr. Klimas said they were  going to try and sell the project to Medicare.

The ability to do this kind of work is one of the dreams of the electronic digital revolution spreading across the medical field.  Only time will tell but hopefully it will deliver on its promise.

How did Dr. Klimas get this project up and running? She walked into an NSU office…and asked them “Do you think we could????” and it was borne. That’s the difference between working in a pro-active environment that is eager for you to succeed and in an institution (my words, not hers) that tolerates your existence but isn’t going to go out of its way to support you.

Other Goals

  • Establish a Translational Research Program
  • Begin the DOD modeling studies (see later presentation)
  • Establish a Nanostring (Gene Expression)  Laboratory
  • Integrate DOD and NIH programs at the new lab
  • Apply to NIH for Program Project Funds to Pull Everything Together
  • Train Young  Researchers

Five Year Goals

  • Be a self sustaining unit without the need for extra University funding
  • Develop funded training program for young faculty
  • Creating an endowment that supports the program
  • Broaden international collaborations
Dr. Klimas goal is to create a environment that fosters communication and innovation

Dr. Klimas goal is to create a environment that fosters communication and innovation

Conclusion

Dr. Klimas is getting good support, the Institute is growing rapidly, it’s involved in many studies and it’s got big plans. 2012 was a good first year for the Institute for Neuroimmune Research.

Next up: Dr. Hornig on Autoimmunity and ME/CFS