Dr. Susan Vernon and Dr. Lucinda Bateman spoke in Denver on Saturday, June 28. Dr. Bateman gave a presentation on research out of the University of Utah she co-authored in her talk, “Treatment Options for ME/CFS and Fibromyalgia patients
I took two main points from her presentation. The first was her strong emphasis on using “pacing” to mitigate the “crash and burn cycle” which can be so damaging to ME/CFS patients (and a cycle that I cannot seem to avoid.) The second point I took regards gene expression studies that incorporate exercise to dramatically highlight subsets….which I am going to explore in this blog.
In her talk Dr. Bateman presented PowerPoint slides from the paper, “Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome” that she co- authored with Dr. Light of the University of Utah, and can be found .
This is not “new” research; this blog is a look back at a piece of research that affected me powerfully.
Dr. Bateman supplied the patients for this study. Dr. Light had them do moderate exercise on a stationary bike and then compared their gene expression profiles before, during and after exercise to those of healthy controls. They concentrated on three groups; people with fibromyalgia, people with fibromyalgia and ME/CFS, and a control group of healthy people.
An Orthostatically Intolerant Group Stands Out
They started with three groups but the results allowed them to separate the fibromyalgia and ME/CFS patient group into two additional subgroups. This blog is about one of those subgroups which had two unusual characteristics; the activity of one specific gene was decreased and 2/3rds of this group had orthostatic intolerance (POTS).
Kim McCleary, the former President of the CFIDS Association of America’ posted an excellent summary of this research. Here is Kim’s summary of that subgroup (emphasis added by me):
α-2A Decrease Subgroup (14/48 CFS subjects): The majority of this group (71%) also had clinical orthostatic intolerance (which) “suggests that different mechanisms cause the debilitating fatigue in this subgroup. The large decreases in α-2A may reflect a particular type of dysregulation of the sympathetic nervous system.” The researchers suggest that an effect of this dysregulation would be the “inadequate blood flow to the working muscles and the brain” that has been reported by other groups in some CFS subgroups. They state, “The relationship between α-2A decrease CFS patients and postural orthostatic tachycardia syndrome and the degree and type of autonomic disturbances needs further study.”
The radical difference in the gene expression results from the “orthostatic Intolerance” group and the others can be seen in this stunning set of graphs below (The “orthostatic Intolerance” patient subgroup is set “C“).
Note how similar all the groups looked prior to exercise. During and after exercise gene expression skyrocketed in the biggest CFS/FM group, but only two genes really went out of whack after exercise in Group C. Decreased expression of the alpha-2a receptor gene (note the descending purple bars) during exercise was found in this group and only this group. That gene definitely did not kick in for that group during exercise.
I’ve always been fascinated by colorful charts and graphs maps, but this dramatic visual display of what may be going on in our bodies really stunned me. When this study was published I put a copy of the graph showing patient group A and B on my refrigerator.
For the next six months whenever somebody new came in my house and commented “What is this colorful graph?” I would take it and say, “Look! This is what is wrong with me when I exercise or perform some muscular exertion. This is why I feel like crap and crash for the next couple of days. Finally some researchers have shown why!” Of course, they would not really understand what is going on in these studies; hell, I barely comprehend it, but they can see the control group and they can see the patient group, and they can see the huge difference between normal people and the patient group.
The POTS Group?
This group was called the orthostatic intolerant group, but in fact they were really POTS patients. Dr. Bateman explained that their heart beat increased about 28 bpm when they stood up which is just under the accepted medical definition for POTS of a 30 beat per minute elevation, thus their use of the term, “orthostatic intolerance”.
The Adrenergic Alpha 2A Receptor
Before we get going on what the alpha 2A receptor does, we should understand what receptors do. Think of cells as listening devices primed to respond to changes in their environment and receptors as being their ‘antennae’. Once the receptor is triggered by a substance the cell goes into action…pumping out cytokines or hormones or whatever that receptor tells the cell to do.These researchers picked receptors they knew played a role in the exercise response.
In this case, the adrenergic alpha 2A receptor is being under-expressed; ie when the call came to assist in exercise the AA2a receptors did not pick it up.
Found in both the central nervous system (including the brain) and the peripheral nervous system in the body, the adrenergic receptors and the neurons they’re associated with, impact many areas of the body. The alpha 2A receptors decrease sympathetic outflow and blood pressure, whereas the alpha 2B subtype increases blood pressure. Also, they regulate the inhibitory presynaptic feedback loop that controls neurotransmitter release from adrenergic nerves. The key point is that activation of these receptors inhibits the release of norepinephrine.
Since norepinephrine activates the sympathetic nervous system, the reduced alpha 2a receptor expression in the subgroup suggests norepinephrine levels and sympathetic nervous system activity are increased in the POTS group. Let’s see what effect that might have. From Wikipedia:
Norepinephrine is also used as a vasopressor medication (for example, brand name Levophed) for patients with critical hypotension. It is given intravenously and acts on both α1 and α2 adrenergic receptors to cause vasoconstriction. Its effects are often limited to the increasing of blood pressure through agonist activity on α1 and α2 receptors, and causing a resultant increase in peripheral vascular resistance.
They’re saying that norepinephrine can be given intravenously (with great care) to patients that have life-threatening low blood pressure to constrict the peripheral vascular system in order to increase the blood pressure in the arteries.
If you look on YouTube and find the video where Dr. Kenny De Meirleir talks about blood circulation and ME/CFS, you will hear him say that some of his patients have constriction of the peripheral vascular system because the larger blood vessels are dilated too much, or you can read Cort’s summary here.
Dr. DeMeirleir appears to suggest that blood vessels elsewhere are tightening up furiously in order to get blood to the brain. That scenario fits this subgroup of POTS patients with an over active sympathetic nervous system who are unable to stand without symptoms.
Here There and Everywhere
The sympathetic nervous system appears to be involved in multiple ways in ME/CFS. Try reading Cort’s blog suggesting that an overactive sympathetic system and peripheral system vascular dysfunction may be causing pain, or my recent blog on allodynia (a common symptom in fibromyalgia) which suggests that vasospasms in capillaries due to a dysfunctional autonomic system result in ischemia, reperfusion, and pain issues including allodynia.
A Clinically Definable Subgroup
So, we have a ME/CFS subgroup, some mounting research evidence, and two experienced clinicians, Dr. Bateman and Dr. Kenny De Meirleir, who appear to be finding the same issue in a subgroup of their patients. This is a subgroup of patients that any clinician can easily diagnose. The subgroup has three easily diagnosable characteristics;
- postexertional malaise
- muscular pain (perhaps allodynia)
- orthostatic intolerance.
Perhaps the most intriguing thing about this group is that it’s primarily defined right now by the declines in the expression of just one gene. That means this group, which may very well be the most debilitated one, is potentially the simplest to understand and the easiest to treat. It’s possible that a drug manufactured to target just that gene could pop that group right out of their exercise intolerance. Much more study, of course, is needed to validate that finding and check if other genes are involved. Another study is underway to do just that (see below.)
An Easily Diagnosable Patient Group. Is This Not What We Are Looking For?
This is not rocket science; we just need more experienced and educated clinicians. Orthostatic intolerance, after all, can be pretty easily measured with a simple heart monitor and doing a poor man’s tilt table test. Muscular pain and postexertional malaise can be easily determined from a quick patient interview and history.
Good luck on finding that medical doctor who will do this, though. Climb a mountain top and proclaim to all when you do find one.
The Clinician Deficit
I asked my “CFS/FM specialist” to distribute the notice of the presentation by Dr. Vernon and Dr. Bateman to her associates in the University of Colorado Healthcare system, which consists of hundreds, if not thousands of doctors and medical researchers. Did any of them show up? No. The room was full of families of patients and patients, and not a medical doctor to be seen anywhere, except for Dr. Bateman.
Dr. Bateman gave an enlightening presentation in Denver. I interrupted her at one point and asked her how many medical doctors had she given this presentation to? She squirmed and looked uncomfortable, but eventually said that she had not given this presentation to any medical doctors, yet. I understand that this is a new presentation and it was only the second time she had given it, but I got a strong feeling she was planning to give this presentation to only patient groups, not clinicians. As much as I loved learning what she had to present, you and I both know that the patients are pfar more educated about ME/CFS/FMS treatment as a group than clinicians.
My Recent Experience as Example
My symptoms meet the definition of the orthostatic intolerance subgroup Dr. Bateman’s study delineated. After searching and going through doctor after doctor for years (sound familiar?) I finally stumbled upon an experienced cardiologist who seemed worth a shot.
The cardiologist walked in, I told him about my orthostatic intolerance, cold extremities and showed him some heart monitor graphs. He listened carefully. He put a stethoscope to my heart and said that I had a mitral valve prolapse, which is commonly found people with low blood volume. He examined my medical chart and history, scratched his head in confusion at my medical history and then said this:
“You most likely have low blood volume, and possibly your large blood vessels are vasodilating causing your peripheral vessels to vasoconstrict. The first thing we will try to do is to raise your blood volume then once it appears to be near proper, we will see if we can try to get more blood to your peripheral vascular system.”
No fancy tests, no blood draws, no rocket science, just an experienced and caring physician.
We Need Clinicians Now
We need an ongoing system to develop knowledgeable and competent clinicians. I’ve heard Dr. Klimas and Dr. Bateman both state that they can significantly improve the quality of life of many of their patients. What if we had a system that multiplied the number of experienced clinicians by a few thousand?
Let’s suppose that all that orthostatically intolerant group identified in this study really needs is a drug targeting the activity of that one gene. If networks of ME/CFS knowledgeable physicians were available not only would patients would be more functional the day that drug became available, but a way of getting the word quickly out to them would already be in place. Otherwise, you are going to be back in that medical doctor’s office with a stack of papers about the Holy Grail Cure and trying to negotiate with him (or her) to take a look at this new information within the allocated 10-15 minutes you have with him.
We need one of the national organizations to put the time and money into educating clinicians now, not later.
The Lights are engaged in two studies that will further their findings. One expanded version of the study under discussion study will add 140 subjects to the 170 person database they already have. This study will involve full genomic arrays plus targeted genes (including some new ones) to see if ME/CFS patients can be differentiated from healthy controls, people with depression and cancer patients with fatigue during and exercise challenge. It’s due to end in August of next year.
Another study seeks to uncover how neurons on muscles detect and transmit signs of muscle fatigue to the central nervous system and how abnormalities in that system can produce excessive fatigue.
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