The Complex
Is ME/CFS/FM bigger than we think? Does it consist of a complex of disorders such as ME/CFS/FM/POTS/Autonomic Neuropathy/IBS/ (fill in the blank) that share similar types of onset, symptoms and some lab results. Let’s see how that question is shaking out.
Infections are the Most Common Trigger of POTS
Infections don’t just trigger ME/CFS; they also commonly trigger POTS, fibromyalgia and autoimmune disorders
The more you look, the more you find. We know infections are common triggers of chronic fatigue syndrome, autoimmune disorders, fibromyalgia, and autonomic neuropathy. Now a very large Johns Hopkins /New York Medical College study reveals that more cases of POTS are triggered by an infection (infection-45%, viral-31%, bacterial-14%) than by anything else (surgery or trauma – 26%) and puberty (22%). One wonders how many other chronic illnesses are triggered by infections.
The surgery connection is interesting given the discussion I recently had with a doctor associated with Daxor Corporation, a company that produces a semi-automated Blood Volume Analyzer, who noted the stress surgery often imposes on the cardiovascular system.
The fact that women tend to need more transfusions after surgery suggests they may have more problems maintaining blood volume than men. (It also suggests that blood volume is rarely checked prior to surgery.) One wonders if pre-surgical patients should be routinely asked if they have symptoms of orthostatic intolerance, and, if they do, have their blood volume levels checked.
The connections between ME/CFS, FM, POT and several autonomic nervous system disorders are growing….
The POTS and ME/CFS Complex
The same study found ME/CFS diagnoses were very common in POTS (33% of POTS patients), but that migraines are even more commonly found (45%). With a recent study finding a high prevalence of migraine in ME/CFS and all three disorders sharing problems with blood flow, the autonomic nervous system connection is growing ever more interesting.
ME/CFS was the second diagnosed disease but Ehlers-Danlos Syndrome (hypermobility), a much less well known disorder, was present in a surprisingly high (29%) percentage of patients. Gastrointestinal reflux, IBS, and sleep disorders were also commonly found. It is interesting that high rates of food intolerance were found in POTS, with dairy (44%) and wheat/gluten (29%) leading the list.
Very high rates of fatigue (70%), lightheadedness (60%), brain fog (52%), and gut problems (43%) rounded out a symptom picture very similar (high fatigue, brain fog, gut problems, etc.) and yet different (high lightheadedness, little pain, no PEM mentioned) than found in ME/CFS. One wonders how much post-exertional malaise lay buried under fatigue
The POTS, ME/CFS, FM, and Autonomic Neuropathy Complex
Another study of people with autonomic neuropathy (damage to the autonomic nerve fibers) found similar co-morbidities to those in POTS. They included chronic fatigue syndrome, migraines, fibromyalgia, gut problems and others. Several studies this year found high rates of small fiber neuropathy in fibromyalgia. If those studies are validated, expect the ME/CFS, FM, POTS, and Autoimmune Neuropathy connection to grow and grow. We expect to hear more from Dr. Sivieri and Dr. Teitelbaum on their experiences looking for and treating SFN in ME/CFS and FM patients by next year.
The Gut-Brain Connection
No less than 10-20% of the population suffers from ‘functional gastrointestinal disorders’ such as IBS, chronic unexplained nausea, ‘abdominal migraines ‘ (!) and functional dyspepsia. (Abdominal migraines are more commonly found in children, often run in families with migraines, are often preceded by an aura, and are accompanied by acute, severe abdominal pain, nausea, vomiting, paleness, and inability to eat.) In the absence of clear gut pathology, understanding these ‘extremely complex’ disorders has been difficult. But in the past 1-2 decades, research is pointing at the brain-gut connection, and the gut flora (gut microbiome).
A genetic predisposition to these ‘functional’ disorders is assumed.
The current belief is that genetic or epigenetic factors predispose a certain percentage of the population to coming down with a ‘functional disorder’. (Hopefully, the term ‘functional disorder’– which refers to a disorder that reduces functioning without laboratory evidence indicating why – will be retired at some point.)
It happens something like this: a first hit (infection, toxin – some sort of stressful event) that produces few symptoms occurs and the individual appears to recover, but the groundwork for disaster has been laid. Later, a second hit – an illness, stressful emotional event, etc. – triggers the occurrence of a ‘functional gastrointestinal disorder’, or in many cases a ‘functional disorder syndrome’ such as IBS plus ME/CFS, fibromyalgia, migraines, POTS, or others.
Some researchers believe a similar process – a series of infectious events that primed the system, so to speak, to collapse – commonly occurs in ME/CFS. Dr. Chia, in particular, has talked of a series of infections that get worse over time. Dr. Pridgen’s entrée into fibromyalgia involved watching his gut patients respond to his treatments only to relapse and then get worse with the advent of a stressful event. It was that pattern of relapse/improvement/bigger relapse/less improvement/even bigger relapse that led him to propose that a spreading viral infection causes fibromyalgia.
Several factors seem to prime the system to collapse in these gut disorders, including adverse early life events, alterations in the gut flora, and (get this!) glial pathways and sleep disturbances. Poor sleep, in particular, appears to set the stage for functional pain and fatigue disorders.
“The enteric nervous system represents a unique component of the autonomic nervous system”
Animal studies are beginning to reveal how this happens. Laboratory animals exposed to stress, inflammatory, or postinflammatory conditions undergo changes in their gut, secretory, and sensory nervous system pathways that result in long-term disruptions in gut functioning and heightened sensitivity to pain. Altered gut serotonin signaling and an as yet unidentified neuroactive factor both appear to play major roles in this ‘neural sensitization’ process. (An extract from the gut mucosa of IBS patients provokes unusual responses in healthy gut neurons, but the factor tweaking the neurons that has not yet been identified.) That neural sensitization that begins in the gut then spreads to the spinal cord and/or brain pathways.
- Check out how Neuroinflammatory ‘Tracking’ appears to cause the same problem in another autonomic nervous system disorder, CRPS
The Insula is Back – Increased activity in the part of the brain that integrates the sensory inputs from the body, the insula, is showing up in all these disorders. Altered activity in the insula appears to be associated with increased pain levels and hyper-awareness of sensory signals coming from the gut. IBS patients also share with FM, ME/CFS and POTS heart rate variability and reduced vagal tone.
Whoops – Drug Induced Autonomic Nervous System Failure Puts Woman in Wheelchair
This is an extraordinary drug interaction involving two relatively commonly used drugs leading to a devastating complication. Infections, concussion, injuries, and cancer treatments appear to be able to trigger a kind of long-lasting system reset of one form or another in chronic fatigue syndrome, fibromyalgia, POTS, autoimmune disorders, etc.
The wrong drug combination basically blew one persons autonomic nervous system to smithereens…She recovered completely after getting off one drug.
The case report below suggests drug combinations in susceptible individuals can essentially blow their autonomic nervous system to smithereens. If you had ME/CFS and then developed OI sometime after you started a new drug treatment, you might want to think about this woman’s case.
It all began for one 18-year-old Texas woman who showed up in a wheelchair at an Autonomic Clinic (Autonomic Function Clinic) with extremely low blood pressure upon standing. This woman was a mess; she’d been unfortunate enough to come down with leukemia as well as migraine, avascular necrosis, obsessive-compulsive disorder, anxiety, depression and increased weight.
She was taking no less than 10 prescription drugs (midodrine, fludrocortisone, fluvoxamine, desvenlafaxine, clonazepam, topiramate, drospirenone/ethinyl estradiol, tizanidine, zolpidem, and oxycodone.)
Upon standing her blood pressure fell from 118/70 to 50/33. She lasted about 2 minutes standing before fainting and going into convulsions. Once she hit the ground her blood pressure recovered quickly. Autonomic testing (the kind Wellpoint Insurance is no longer covering – see here) revealed ‘dense sympathetic autonomic failure’. Her initial diagnosis was autoimmune autonomic ganglionopathy.
The doctors noted, however, that fluvoxamine decreased tizanidine clearance, which suggested tizanidine might be rapidly increasing in her system. Even though tizanidine is not believed to affect the autonomic nervous system, they took her off it. Two weeks later she was shopping and exercising without symptoms. After standing for 10 minutes her blood pressure was the same as when she started.
The doctors conjectured that at very high levels tizanidine can indeed affect the autonomic nervous system. Add drug interactions to the list of stressors that can trigger dysautonomia. The takeaway point: watch your drugs closely and don’t even begin to think our understanding of what they do is complete. If you have autonomic nervous system problems, you might consider monitoring your symptoms over time. It appears that a portable autonomic nervous system monitoring system may be coming to your doctor’s office soon.
Being ‘Smart’ About Your Autonomic Health
The first mobile autonomic nervous system monitor may be coming to your doctors office soon
The Department of Biomedical Engineering at Vanderbilt University (no surprise, there) has built a ‘low-cost’ miniature device that interfaces with your smartphone (of course) to monitor your autonomic nervous system. It monitors your blood pressure, uses high-quality ECGs to monitor heart rate, stroke volume of your heart, ‘body impedance’, as well as fluid shifts when you stand, sit down, etc. It allows you to input your symptoms and maintain a diary. It can be programmed to detect fluid shifts and falls in critical blood pressure values that may precipitate a faint or fall, and sound an alarm urging you to sit down immediately. Hopefully, it will be coming to your online app store soon.
- Check out Pt I of the Autonomic Nervous Symposium Overview
- Coming up soon – An Interview with Dr. Julia Newton
Great stuff Cort.
I know you’ve a blog coming up soon on microglia (really looking forward to that one). I’ve come around to thinking that primed/activated microglia and astrocyte dysfunction are where its at with ME/CFS, fibro and a range of other conditions with overlapping symptoms.
Microglial activation potentially bridges the gap between a range of apparently unrelated triggers and chronic multi-symptom/multi-system ‘syndromes’.
Your quote :
“It happens something like this: a first hit (infection, toxin – some sort of stressful event) that produces few symptoms occurs and the individual appears to recover, but the groundwork for disaster has been laid. Later, a second hit – an illness, stressful emotional event, etc. – triggers the occurrence of a ‘functional gastrointestinal disorder’, or in many cases a ‘functional disorder syndrome’ such as IBS plus ME/CFS, fibromyalgia, migraines, POTS, or others.”
It seems that a range of ‘stressors’ (infection, psychological stress, surgery, injury/accidents and potentially cancer treatments) can ‘prime’ microglia in the brain to be ‘hyper-responsive’ to subsequent infections or tissue damage with heightened ‘sickness behaviour’.
Stressors include normal aging where the elderly have an exaggerated response to previously trivial illnesses.
Ever wonder why the elderly often have such a precipitous physical or mental decline after a fall for example?
“Thus, the aging process appears to serve as a “priming” stimulus for microglia, and upon secondary stimulation with a triggering stimulus (i.e., peripheral signals communicating infection), these primed microglia release excessive quantities of proinflammatory cytokines. Subsequently, this exaggerated cytokine release elicits exaggerated behavioral changes including anorexia, hypersomnia, lethargy, decreased social interaction, and deficits in cognitive and motor function (collectively known as the sickness behavior syndrome).”
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2538600/
Thanks again, Mark….Man, I think we’re getting closer – I really do. I’m getting those tingles up my spine 🙂
Tingling spine?
Sounds like neuropathy : )
Joking aside, microglial activation is a theory that can be tested. Or may have already been?
Hip posted a link to this study some time ago. I can’t access the full text but I believe it was a positive finding :
Microglial activation in patients with chronic fatigue syndrome: A positron emission tomography study with [11C]PK11195
http://www.sciencedirect.com/science/article/pii/S0168010211010455
How do you find this stuff? I’m going to see if I can get it…That’s really something.
Ha! I found the abstract. I don’t know what it means, but here it is…
Chronic fatigue syndrome (CFS) is an illness characterized by a profound, disabling, and unexplained fatigue lasting at least 6 months, which severely impairs daily functioning.
Anatomical and/or metabolic impairments in the central nervous system have been reported in the patients with CFS. Based on the results of our previous studies, we hypothesized that microglia cells, the macrophages of the brain, are activated by inflammation of the brain in these patients.
Since microglial activation can be evaluated in vivo by using [11C]PK11195 which is the positron emission tomography (PET) ligand for the peripheral benzodiazepine receptors expressed in activated microglia cells, we tried to determine whether microglial activation occurs in these patients.
Binding potential of [11C]PK11195 in the left thalamus was increased as compared with those of the healthy participants; and the binding potential tend to be negatively associated with the daily functioning level assessed by performance status in these patients.
Microglial activation was shown in these patients and this activation might contribute to the pathophysiology of CFS.
Ha! you guys are funny. I also think the answers are very close to being discovered. I know there is a connection with all of it. The pieces of the puzzle are coming together.
Those in the POTS world know that I question the meds that are being given. If what our bodies are doing is a compensatory thing and you suppress that response, the long term consequences may be even worse than the illness. They give one med for one thing and have to keep adding meds for the side effects. Long term, this just can’t be good. What our bodies are trying to do to keep us alive – doesn’t need to be suppressed (although with the tachy, sometimes it’s a relief, if not but for a few weeks, to have it not be so intense). We need to get to the core issue.
The app. sounds interesting. But, for those who are fainters with POTS – sometimes there is not enough warning to get seated. For some of us, we do have enough symptoms that occur beforehand to know when we need to get down. But, it can happen so fast for others that I’m not sure this app. would even help. I personally feel that we shouldn’t get obsessed with our heart rates and pulse response. I have heard of some that are getting dogs to detect issues and they can give advance notice. Besides dogs give unconditional love and it’s nice to have that and their company.
Issie
Thanks Cort for this brilliant summary. The two things getting me excited are the documented evidence of the infectious trigger and the cascade of neural sensitisation. However, it remains to be seen if treatments will follow. As Issie says, all current treatments for POTS only address the symptoms not the cause and if the cause is no longer present, it must the body’s reaction to the cause and how to treat this? I have been reading up on the Gupta method which claims the amygdala is stuck on overdrive in CFS – maybe he’s right but wrong about what part of the brain is on overdrive and by what method the overdrive affects the body. Keep up the good work Cort really appreciate it!
The next year they had another study
Poster Sessions : Neuroprotection, Neurotoxicity and Neuroinflammation (P1-l09)
2012/09/18 00:00-00:00
Neuroinflammation in patients with chronic fatigue syndrome: a positron emission tomography study with [11C]PK(R)-11195
Chronic fatigue syndrome (CFS) is an illness characterized by a profound, disabling, and unexplained fatigue lasting at least 6 months accompanied by a combination of nonspecific symptoms. We have reported anatomical and metabolic impairments in the central nervous system in patients with CFS.
Based on these results, we hypothesized that neuroinflammation in the brain may play a critical role in the pathophysiology of CFS. We tried to determine whether neuroinflammation occurs in the brains of CFS patients using positron emission tomography (PET) with [11C]PK(R)-11195, which is a PET ligand for translocator protein (TSPO), formerly known as the peripheral benzodiazepine receptor, expressed in the mitochondria of activated glial cells.
Level of fatigue sensation using visual analog scale for fatigue and physical activity assessed using actigraph, which is a wrist-watch type accelerometer, were measured before the PET recording.
The patients with CFS showed higher level of the binding potential of [11C]PK(R)-11195 in the intralaminar nuclei of the left thalamus than healthy volunteers; and levels of the binding potential in these patients were positively correlated with those of the fatigue sensation, difficulty in maintaining sleep, and physical activity during sleep.
These data suggest that neuroinflammation in the intralaminar nuclei of the thalamus plays a critical role in the pathophysiology of CFS.
Thanks Cort
Good find.
I’ve just been reading that translocator protein (TSPO) binding (as a sign of activated microglia) can be induced by systemic inflammation – not just local brain inflammation or damage and increased TSPO binding has been associated with patients with stroke, traumatic brain injury and in patients with chronic neurodegenerative conditions including Huntington’s disease and Parkinson’s disease.
The ‘formerly known as the peripheral benzodiazepine receptor’ sounded familiar but I was wrong. I was thinking of Kathleen Light’s recent finding that fatigue severity in CFS and prostate cancer patients seems to be mediated by increased expression of the diazepam binding inhibitor (DBI).
http://www.prohealth.com/me-cfs/library/showarticle.cfm?libid=18413
So no connection there then? – except that DBI appears to be a “potent agonist” of the TSPO receptor : )
Fantastic compilation of articles…glad to see research stretching into how these comorbid conditions (of which I have ALL mentioned above, except abdominal migraines—as far as I know, I don’t have those) relate to one another. It’s crucial stuff.
We need to see more research on genetic (but non Familial) Dysautonomia. I have at least five known consecutive generations of it in my paternal line. Also, no real studies have been published on the so-called puberty induced POTS that people have allegedly completely recovered from, to see how these folks fare over an extended period of time. Dysautonomia can have periods of relapse and remission/partial remission, and can get progressively worse with each ‘flare’ (not unlike MS). Another area that needs, IMHO, intensive study is Dysautonomia in the elderly–many of the symptoms are similar to those used to diagnose Alzheimer’s. I personally believe some folks dx’d with Alzheimer’s may actually have POTS and comorbid conditions. I believe I’ve witnesses this in my family.
Last comment, let’s all push to have the poor man’s tilt test for orthostatic intolerance performed at all annual physicals, particularly during puberty and young adulthood. This screening would go a long way toward diagnosing more effectively and earlier.
Great idea Shae and thanks for all the info 🙂
Fascinating information. Thanks for all the time and effort!! The links are a benefit!
I’m a family doc who started using acupuncture 15 yrs ago to help my FM patients. What a great addition to my armamentarium, but something was still missing. That pointed me to a parallel universe of ideas, causes and therapies that are marginalized by traditional medicine. That is Myofascial Pain and Dysfunction as per Travell/Simons.
As you may know, stressed muscles collect “errors of repair” called Trigger points. TPs generate pain signals; work erratically and spasm out of the blue like in charlie horses or night cramps. They alter “on-off switches” in muscles leading to weakness, more falls, stumbling and “giving-out of a joint.” Stiffness, short erratic muscles are more likely to snap apart, tear and rip off the bone attachments. They make muscles shorter, tighter thus accelerating degeneration and the thinning of cartilage. Correct muscle length is vital for the proper joint alignment, so these shorter stiffer muscles will cause accelerated degeneration of intra-articular structures.
Depending on the length of time, the muscles will evolve from normal soft and supple to dry stiff, dense less capable structures. I like to compare the change from Filet Mignon to beef jerky and you can feel this with a needle. The beef jerky muscles will block normal functions like nerve impulses, artery and venous flow, lymphatic and even chemical, hormonal and immune functions. Today from microscopic tissue samples from infected patients, we know the the cell and possibly the DNA will become corrupted.
Corrupted cellular and subcellular milieu will transform the human entity into a discombobulated being. Overtime the person become even more ill and disabled. The final end result is a complete state of misery called Spinal Segment Sensitization.
Have you heard of SSS?
http://www.scribd.com/doc/51002931/UNDERSTANDING-SPINAL-SEGMENTAL-SENSITIZATION-AS-A-NEW-CONCEPT-OF-PAIN-AND-EMPLOY-ITS-TREATMENT-STRATEGIES
http://www.spinalsensitization.com/method.php
Thanks very much Dr. Rodriguez – very illuminating. I’ll check out those links.