Simmaron’s Pre-FDA Workshop Roundtable: Scientifically Redefining ME/CFS, April 25, 2013
By Cort Johnson
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.
Given the many different types of patients Dr. Peterson sees, the idea of drug trials that don’t establish subsets first is simply appalling. The idea that this complex mix of patients are ever going to respond similarly to a drug is nonsense.“I am very concerned about random drug trials that take the first 100 patients who sign up. It would be a disaster,” said Dr. Peterson.
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.
How to Diagnose ME/CFS: The Immune System
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 to 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.
As an immunologist, it wasn’t surprising to see Dr. Klimas’ 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 immunology work on CFS/ME.
Immune factors are one lab measurement that has to be accurate; tweak the powerful immune system the wrong way and you can cause a lot of trouble. If the physician is 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' lab.
Dr. Klimas will dig into IGG subclasses if she sees bacterial infections. Dr. Enlander focuses 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 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.
What does Dr. Klimas find that correlates 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 a lot about IL-5 but it boosts two immune factors of interest in ME/CFS; mast cells and B-cells. Overactive B-cells have been implicated in 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.
Autonomic Nervous System
After Dr. Peterson stated that 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. Dr. Peterson and Dr. Enlander do 24-hour BP and heart testing, and Dr. Enlander and Dr. Klimas use tilt table testing. Dr. Klimas noted that autonomic nervous system dysfunction appears to trigger immune dysfunction. She asserted that the sympathetic nervous system is a major player in this disorder and she rattled off problems with standing, respiration, poor digestion, etc. that could all be caused by SNS upregulation.
It’s not clear how many of the physicians were measuring blood volume; it may be that they all simply assume blood volume is low. 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.
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.
As the first ME/CFS physician to embrace VO2 max testing, Dr. Peterson made a strong plug for Staci Stevens' two-day exercise test 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 improve of all ME/CFS tests. Since Dr. Peterson finds that low VO2 max scores are often correlated with poor cognition, abnormalities on MRIs 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.
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 had returned to full VO 2 max functioning.)
Dr. Klimas has been digging deep into exercise in her research, which, in turn, is informing her diagnostic work. (This is known as ‘translational medicine’). Earlier this year she reported gene expression studies indicating that the autonomic nervous system drops first during exercise and then drags the immune system down with it.
This major finding, if validated, suggests breakdowns in the ANS, which is tightly intertwined with the immune system, could be at the core of the disorder.
Dr. Enlander is committing a big chunk of money to a sophisticated exercise testing study at the Mt Sinai Research Center. He’s has a geneticist, an immunologist and a pulmonologist all working together.
After having patients exercise, Enlander’s team will be looking at RNA (genes), blood (immune factors, a stool sample, RNA, DNA genome, enteroviruses), brain MRI and SPECT scans. Among other things Enlander will be looking to confirm or deny Dr. Chia’s findings seven years ago of enteroviral infections in CFS/ME patients.
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 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 spinal taps more in the future. Dr. Klimas is waiting to find 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.
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’ (i.e. non-genetic) NK cell dysfunction as well. He believes insights gathered from mRNA in the spinal fluid of ME/CFS patients, for instance, and more rigorous pathogen detection techniques will continue to open up this field and inform his diagnostics.
Similarly, Dr. Klimas’ exercise studies are leading her to focus more on improving autonomic dysfunction in her patients. Dr. Enlander will use his big exercise study to increase his understanding of his patients. Each of these three physician/researchers is eager to incorporate their research findings into their diagnostic protocols.
“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 category as soon as something concrete is found. Stating that this attitude is now prevalent, 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.
Dr. Klimas acknowledged that while getting a diagnosis that can be treated is great, culling out large numbers of ME/CFS patients could be devastating. For one, it condemns ‘ME/CFS’ to be a a mere placeholder of an illness.
Dr. Klimas noted that Dr. Peterson’s finding that 17% of his cognitively dysfunctional patients were culture positive for viruses in their spinal fluid comprised a clear subset. (She was reminded of former CDC CFS chief Bill Reeves' response “you don’t know what doesn’t belong there.” She laughed and said, “Wait a minute. Would it be okay for you to have your cognitively dysfunctional child have a positive spinal fluid test? I don’t think so.”) What a dilemma, she said, that every time we start to get clarity, part of this disorder gets shuffled off into another column.
The Hidden Epidemic
“Talk about a forgotten, ignored group of people.”
Then there are the missing patients; the bedridden ones who rarely get to doctors' clinics and certainly aren’t in research studies. How do you define a disease without access to all the patients? In most disorders, the most severely ill usually get the most attention, but the opposite is true in ME/CFS. (A former ICU nurse working with Dr. Kogelnik remarked that these patients should be in a hospital, not at home.)
Dr. Peterson“The bedridden patients – It’s the hidden epidemic within another epidemic. It’s scary.” Dr. Dan Peterson
Dr. Peterson noted that we don’t have 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 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 during patients' bad days. Both Dr. Klimas and Dr. Enlander said they do house calls from time to time.