Inflammation and Autonomic Dysfunction

The rest of this information is generic and my interpretation of current knowledge. This is not mainstream medicine and as such, it must be read and seen as research-based rather than evidence-based which is how medicine usually works, and which does provide a safety net against extreme concepts.

Working through the problems leading to POTS and fibromyalgia, my primary research areas, is like opening Pandora’s Box – lots of things there! Essentially, we are all born with genetic predispositions to various things depending on our parents, and then it is what activates things- infections, parasites, injuries, other trauma etc etc that sets off the inflammatory pathways, and when this becomes chronic, sometimes mast cell activation chimes in with its own set of responses. This mast cell activation is thought to be present in all POTS, although I do wonder whether it is the cart or the horse in most people. Increasingly I see this response as the body trying to defend itself.

But that becomes academic anyway. Management remains the same – work out the drivers, remove the ones we can, and control the immune response. I think people can be overwhelmed by the vast array of inflammatory things that are activated, and the biochemical changes that come with the underlying genetic stuff, and try to supplement their way out of it all. We need to go to the grass roots.

Firstly – what are catecholamines?

“A catecholamine  is a monoamine, an organic compound that has a catechol (benzene with two hydroxyl side groups at carbons 1 and 2) and a side-chain amine. Catechol can be either a free molecule or a substituent of a larger molecule, where it represents a 1,2-dihydroxybenzene group.  Catecholamines are derived from the amino acid tyrosine, which is derived from dietary sources as well as synthesis from phenylalanine. Catecholamines are water-soluble and are 50%-bound to plasma proteins in circulation. Included among catecholamines are epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine. Release of the hormones epinephrine and norepinephrine from the adrenal medulla of the adrenal glands is part of the fight-or-flight response. Tyrosine is created from phenylalanine by hydroxylation by the enzyme phenylalanine hydroxylase. Tyrosine is also ingested directly from dietary protein. Catecholamine-secreting cells use several reactions to convert tyrosine serially to L-DOPA and then to dopamine. Depending on the cell type, dopamine may be further converted to norepinephrine or even further converted to epinephrine.” source Wikipedia.


Inflammation is at the basis of most disease. Inflammation, the immune response of body tissues to injury or infection, has been an important part of our innate immunity since we were cavemen. Acute inflammation is a normal process that protects and heals the body following physical injury or infection. However, if the agent causing the inflammation persists for a prolonged period of time, the inflammation becomes chronic, which can cause a wide range of problems.

Current disease research revolves around the TLR Receptors (Toll-like receptors) as being threat response receptors activated by threats to the body, whether this be trauma, food (or alteration in our food such as GM and preservatives) we are intolerant of, even stress etc- which provokes an immune response, causing the typical symptoms of IBS, chronic fatigue, migraine, dysautonomia, fibromyalgia, reflux oesophagitis to name but a few. Working out the things that are triggering the TLRs is critical to dealing with these problems. But like Pandora’s Box, when you open this it can be very complicated with the multiple genetic factors, and various drivers we are only starting to work out. But each one you do can improve the quality of life in someone with this immeasurably.

When stress is less, with less production of catecholamines, the stress or fight or flight chemicals from the adrenals (with consequent reduction in activation of TLR’s,) we can often eat the trigger foods, or small quantities, so sometimes it is hard to work out the culprits. Symptoms often disappear when stress is not present, so many people are considered to have only psychological problems, which is often far from reality.

The spine is a major factor in triggering TLRs, especially in migraine and fibromyalgia. This is obvious in people following whiplash and other spinal injury, but it also can be occupational, for example in hairdresser, dentists, nurses, who work with a rotated spine. There is likely to be an increase over future years as people become more dependent on their computers and tablets, while their posture is not attended to.

There is now increasing evidence that nerve compression can promote local as well as remote immune –mediated inflammation, resulting in activation of pain pathways nowhere near the area of compression. Patients with neuropathic pain from entrapment syndromes often present with symptoms outside the innervation area. (1) Slowly progressive mild nerve compression can produce preferential degeneration of small nerve fibres, whereas myelinated axons remain largely intact. As a consequence, changes are not seen on standard Nerve Conduction Studies. (2)

The vascular compression syndromes, most prominently the popliteal and thoracic outlet syndromes are significant co-factors in the symptomatology in POTS  (Postural Orthostatic Tachycardia Syndrome), but it cannot yet be proven that they are the underlying cause. Pelvic Vein Congestion Syndrome (and Nutcracker Syndrome) are currently being investigated.  Ongoing research in other areas especially Fibromyalgia, Migraine and Hashimotos Disease, has found the same vascular compression syndromes in the majority of patients, again suggesting disease activation by production of microemboli and/or inflammatory cascades which are released as the venous blood is released back into the circulation, (or perhaps simply from vessel walls when directly compressed) as well as any of the other inflammatory causes found in each patient. There also appears to be alteration in the autonomic nervous system response when compression is present. (14)

With awareness of the various “drivers”, patients with fibromyalgia, dysautonomia, migraine and POTS are often able to differentiate the different “drivers” to these patterns of their problems. For example, someone with popliteal compression may now recognize the paraesthesiae in their hands or feet with posture, and those with mid-thoracic spine injuries especially around T7 can recognize the tachycardia and wave of anxiety with rotation of the spine. Simply driving with arms outstretched can produce typical symptoms of a panic attack, and weight lifting can produce fatigue, headache and other symptoms. There is of course a blurring of boundaries, but generally as each driver is worked out, these can be nullified or modified by simple changes- most commonly with diet, posture, lifestyle, targeted pilates programs, and above all, knowledge of the underlying causes.

Mast cell Activation appears to be present in POTS patients, and in early studies, in Fibromyalgia and Hashimotos Syndrome. It does provide a plausible explanation for the some of the progressive symptoms, especially the increasing gut, bladder and urticarial symptoms, but when patients as a whole are examined, while it does not provide the complete solution, it allows an insight into the increasing cascade of symptoms and diseases that people develop. It certainly provides an answer to the increased urticariae and IBS symptoms, where as a response to inflammatory things occurring in the body (stress both physical, including infective, traumatic and emotional) mast cells migrate to skin (causing urticaria) and IBS as the body’s recognition of potential food threats is ramped up. There is also the suggestion that this is associated with a physical change to the actual gut lining to explain the “leaky gut”.

“Mast cells play a key role in homeostatic mechanisms and surveillance, recognizing and responding to different pathogens, and tissue injury.  An abundance of mast cells reside in connective tissue that borders with the external world (the skin as well as gastrointestinal, respiratory, and urogenital tracts). Situated near nerve fibres, lymphatics, and blood vessels, as well as coupled with their ability to secrete potent mediators, mast cells can modulate the function of local and distant structures (eg other immune cell populations, fibroblasts, angiogenesis), and mast cell dysregulation has been implicated in immediate and delayed hypersensitivity syndromes, neuropathies, and connective tissue disorders.” (3)

Recently researchers published data linking all types of auto-immune disease in children to the same threat receptors I mention above – so why not in adults? There is a lot of data emerging –slowly, but not linked, so when you put it all together patterns are emerging.

One of the the underlying genetic factor in migraine, and most likely in most of the problems above, appears to be a mutation in the methylation pathway called the MTHFR mutation, which increases oxidative stress. This trait appears to cause a single or multiple enzyme defects in a metabolic pathway (the MTHFR mutation), and it appears that it requires added Vitamin B12 and sometimes others to enhance its function. Dealing with the vitamin processing problems and looking at other causes of oxidative stress, especially from the spine and diet enables these problems to be controlled or significantly improved. Often the simple addition of Vitamin B12 to a migraineur reduces migraine frequency significantly.

Another that has been found to be associated with fibromyalgia are the COMT mutations, where there is a reduced ability to deal with circulating catecholamines. This then results in heightened “fight or flight” activation, and hypersensitivity to things such as sound or light. It is likely to be associated with sleep disruption as the innate immune system is primed ready to deal with whatever happens in our lives.

Carrying on from Dr David Grosser’s work on popliteal vein compression syndrome, we are finding a very high association between the MTHFR mutation and presence of this compression syndrome, responsible for higher DVT risk, lower leg/foot pain at night and probably restless legs. It is a previously unrecognized cause of increased inflammation in the body, and probably ranks with sleep apnoea and PFOs in inflammatory risk.(4)

Thoracic outlet syndrome has been recognized for decades, but only since we started looking at the inflammatory response in popliteal compression in migraine has this area become more important. Illig and Doyle(17) write: “the subclavian vein is highly vulnerable to injury as it passes by the junction of the first rib and clavicle in the anterior-most part of the thoracic outlet. In addition to extrinsic compression, repetitive forces in this area frequently lead to fixed intrinsic damage and extrinsic scar tissue formation. Venous thoracic outlet syndrome progressing to the point of axillosubclavian vein thrombosis, variously referred to as Paget-Schroetter syndrome or effort thrombosis, is a classic example of an entity which if treated correctly has minimal long-term sequelae but if ignored is associated with significant long-term morbidity.”(17)

In an extreme form of POTS in one of the patients seen, the finding of recurring cardiac failure when lifting repetitively followed a severe shoulder injury and damage to her thoracic outlet. The mechanism in the cardiomyopathy appears to be similar to that in Takotsubo Cardiomyopathy, thought to be a sudden release of cascades of catecholamines. Even partial compression would appear to activate receptors and catecholamine release. Early studies using heart rate variability to measure changes in autonomic tone in the vessels shows 2 distinct patterns, one obviously increased adrenalin, but in others a reverse type of picture. There are also no controls tested, so it is not known if these autonomic changes are “normal.” We certainly need a lot more work done in this area.

We have NO data on this as yet, whether it is the compression of the vein itself, or microemboli released after the vein is compressed and the vein distal to the compression dilates and fills, or more likely both, with microemboli being filtered in the lungs producing inflammatory responses, and compression on veins/ nerves triggering receptors lining these vessels, and then the threat receptors and their inflammatory responses.

Doctors look at people and look for creases in ear lobes as traditionally it signifies the likelihood of vascular disease. This may be wrong, as it may reflect collagen dysfunction, and it just so happens that there is an increased risk of vascular disease in this group. If you think even more broadly, it could explain the modern disease of diverticular disease, polyps, and even the increased numbers of people with food intolerances/ IBS. I theorize that in this group the gut lining is less effective at keeping out the toxins from the foods we eat, and then these chemicals cause inflammatory reactions in the body which simply compound the problem, triggering those very same threat receptors. The reactions to foods the body considers a threat increases through the mast cell activation and increased numbers of these cells in the gut lining.

Diet plays a major component in all inflammatory disease. There is increasing evidence that vascular disease, even hypertension, is inflammatory. Carotid thickness scans can be used to watch for progress in the blood vessels, retinal photos for small vessels, and echocardiograms with ultrasounds of the ascending aorta and these are easy measures to determine if the treatments are working in our hearts and vessels. Bonn University has achieved quite a bit using the same carotid scans and demonstrated that the Mediterranean diet also improves carotid thickness. The same diet reduces the risk of breast cancer by 68%.

Having variable arthritis- wherever, suggests a dietary cause. Having positive antibodies to the thyroid (Hashimotos thyroiditis) implicates an inflammatory and usually there are dietary components. The trick is to find the culprits here. Everyone is off doing gluten and dairy free diets, but most are wrong. It may be cow milk, as this is the first “toxic” chemical the body is exposed to in life, but after that there are many possible. Research in 1999 by Dr David Freed showed the deadly nightshades, the lectins, to be triggers to a wide range of autoimmune disease. But everyone has different triggers, and using the same diet in everyone simply does not work.

Migraine and PFO

When a patent foramen ovale is present between the atria of the heart, microemboli from the vascular compression syndromes shunting through this into the brain may be responsible for cerebral damage particularly dementia, certainly the “stroke-like” symptoms that affect some migraine sufferers. In the brain MRI, migraine sufferers may have white spots, FLAIR hyperintensities. Often labelled as small vessel disease, they can also reflect microembolic damage from the compression syndromes, but can also reflect “vasospasm” from the inflammatory chemicals (without a PFO).  Current unpublished research suggests 60% of severe migraine with aura have associated popliteal compression. We are currently reassessing the other vascular compression areas for this. Unfortunately the current level of radiology does not allow us the ability to differentiate between these, so you have to look for other clues. For example, retinal photography provides an answer to whether there is small vessel disease as in the retina, you actually see the vessels themselves. Unexplained lung damage including emphysema, pulmonary hypertension and fibrosis are probably associated with this microembolic phenomenon.

Thoracic Outlet Compression

There are no population studies looking at the incidence of thoracic compression in the community, and it does appear to be far more extensive than I could have even imagined. It is probably involved in frozen shoulder (adhesive capsulitis) through autonomic responses, and it has been shown to be a cause of unexplained depression and anxiety. Among the worst affected people with POTS are the ones with shoulder injuries so it may be a factor in depression in occupations such as football, or servicemen. This area will be the subject of further studies.

I can find no incidence studies in syncope in people in public transport who travel with arms up holding straps, but I think we will find it there. Many of the POTS patients reported pins and needles (paraesthesiae) in their hands/ arms driving or lifting forward, and there was often unexpected fatigue and sometimes shortness of breath with elevated arms, or arms down carrying weights (eg shopping or wheelbarrow use)- and this has been clearly shown in this study, including panic attacks driving with outstretched arms. As this reflects thoracic compression- caused inflammatory responses, it may suggest a possible cause for driver fatigue, and just may be a contributor in post-natal depression with changes from the pregnancy, then repetitive lifting of increasingly heavy babies. As well, studies during pregnancy have shown compression of pelvic veins by the uterus.

Pelvic Congestion and Nutcracker Syndrome

Pelvic congestion syndrome is associated with chronic pelvic pain secondary to pelvic vein insufficiency and associated pelvic venous distension. Severe orthostatic intolerance may be accompanied by left renal vein occlusion, and chronic fatigue has been associated with high left renal vein- IVC pressure gradients.  (15)

Other symptoms include noncyclical, positional lower back, pelvic, and upper thigh pain., worse before or during menses and may be associated with dyspareunia, and prolonged post-coital discomfort. Symptoms are usually worse at the end of a day, exacerbated by standing or heavy activity, and reduced by supine positioning. Other symptoms include lumbosacral neuropathy, urinary frequency and generalized lethargy. Vulvoperineal varicosities may be seen over the buttock, postermedial thigh, and most commonly manifest during pregnancy and regress postpartum. (16)

Nutcracker Syndrome, the compression of the renal vein into the inferior vena cava can produce the same orthostatic symptoms as POTS. Pelvic vein compression certainly warrants a closer look, particularly with possible implications of post-natal depression (along with thoracic outlet compression), gestational diabetes and PET.

Similar findings were found from popliteal compression, with simply standing in a line for long periods, or sitting watching TV with knees straight and legs extended provoking headaches, anxiety, neuropathic symptoms, hypersensitivity to sound and light, sleep disruption etc.


Shoulder pain is just so common, often not improved and even worse with our normal shoulder treatments, but retracing the injuries there is often a thread implicating an injury to the thoracic outlet rather than the shoulder itself, and as the rotator cuff wears anyway, this ends up as a diagnosis as scans show worn rotator cuffs, so the real problem is missed, and it becomes a treatment failure.

The overwhelming evidence from the POTS study (14) showed the presence of one or more vascular compression syndromes in all patients. It cannot be assumed that these are the cause of POTS, but I do believe they are a significant manageable factor. Pelvic Congestion Syndrome is highly likely to be associated with this, and I expect we will ultimately find this to be every bit as important, (possibly more so depending on severity,) than the popliteal and thoracic compression, which was assessed.

During the study, it was trauma to the neck and shoulders that appeared to provoke the most significant symptoms in patients. The spine is a major factor in triggering TLRs in all the problems of POTS, dysautonomia, migraine and fibromyalgia. This is obvious in trauma especially MVAs, but it also can be occupational, for example in hairdressers, dentists, nurses and supermarket cashiers, or in people working on computers. Increasingly symptoms, including mood disorders can be provoked with the increasing use of smart phones, hand held computers and tablets. Posture is becoming an increasing problem with these devices, and I anticipate increasing problems with spine-driven problems in the future.


The treatment of POTS and all these inflammatory problems should be aimed at removing the driving factors rather than looking for a medication to control symptoms. Of course if your thyroid is destroyed and not functioning, you will need Thyroxine replacement, or in vascular disease the statins Crestor and Lipitor do have anti-inflammatory effects in the vessels, reducing plaque (forget the word cholesterol), the ARB blood pressure medications probably repair the DNA in damaged vessels, and aspirin reduces cancer risk with its anti-inflammatory actions as well as known anti-stroke and infarct risk. The boundaries are blurring in management as well.

At the end it is at its core quite simple – work out the drivers, especially in the spine and vascular compression, sort out dietary triggers, look at lifestyle, posture, occupational causes, supplement where necessary, and heal what has been damaged, if this is possible. Acupuncture, targeted physiotherapy, improved diet lifestyle, occupational and similar changes allow for management based on cause, not symptoms.

High-level acupuncture is invaluable in reducing autonomic and inflammatory responses in POTS while causes are chased. There are a few physiotherapists sufficiently skilled to work out the spine and thoracic drivers, but these therapists deal with the mechanical causes. Generic pilates and exercise programs often do more harm than good. There are even fewer dieticians capable of sorting out the food intolerance drivers when present, but they are around. At present, the research continues, but the knowledge that the popliteal compression can usually be managed by positional change (4), and the thoracic outlet by awareness and improved by suitably trained physiotherapists should provide a useful start for clinicians, while looking at other drivers in each patient.


This POTS study implied that searching for causes and drivers to POTS, migraine, fibromyalgia and similar problems enables better management opportunities that trying to add drugs, or supplements. This is an evolving science, and I have no doubt further research will unlock even more causes.

Associated with all of this I think we will need to have a good look at the real cause of diseases such as diabetes, hypertension, cardiomyopathy, COPD, vascular disease and auto-immune disease just to name a few. Anything where there is the word “idiopathic” is a good place to start. These are all inflammatory processes with multiple causes, most importantly genetic, and it is injury, lifestyle and similar factors which steer you into whatever disease you may develop, dependent on your individual DNA.

The work I am doing which is based on current and recent research, much of it at the universities at the Gold Coast and by individual researchers. There are no Cochrane Guidelines here, as it is an evolving management process, so little has been formally adopted in conventional medicine.   More information is available on my website


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