Joining the Dots in POTS, Migraine and Fibromyalgia
One of the safest aspects about modern medicine is its conservatism, and the need to work within accepted and proven guidelines. It is a safeguard against enthusiastic or entrepreneurial management, and usually protects against unsafe and dangerous practices. But its focus is usually limited to single “specialty” areas eg cardiology or neurology and these alone cannot hope to explain the complexity of POTS, fibro, autoimmune disease etc.
There simply so many people in the community with symptoms that reflects the spectrum of POTS symptoms, usually undiagnosed, and certainly undertreated. These drivers discussed here are, I have no doubt, implicated in a wide range of other problems such as dysautonomia, hashimotos and other autoimmune disease, diabetes, Parkinsons disease, and aortic arch/root dilatation and so many more.
Fibromyalgia is found in over 50% of POTS patients and migraine in over 60% – and in migraine 45% have evidence of MRI brain hyperintensities which may reflect microembolic or inflammatory damage (as well as the usual diagnosis of aging small vessel disease.) Common co-morbidities include IBS, fatty liver, Hashimoto’s disease, and there are a few with non-epileptiform seizures.
Working through the problems leading to POTS and fibromyalgia, is like opening Pandora’s Box! But I have found that looking at the activators and drivers in these problems helps us take the next step forward towards recovery. The process is complex as so many processes are underway and all need to be sorted out.
We are all born with genetic predispositions to various things depending on our parents leave us (and until we can manipulate DNA on a wider scale, we have to work with the cards we are dealt), and then it is what activates things- infections, parasites, injuries, mould, sustained stress, trauma especially to the spine and shoulders, even our posture and what we do at work and play that sets off the inflammatory pathways.
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. The work from Griffith University has turned up genetic faults in the TLRs that are undoubtedly contributory in POTS and FMS as well as their own project in Chronic Fatigue Syndrome (CFS.)
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. You may be aware of the increasing food intolerance you are experiencing, but removing physical drivers can slow this down so gradually these intolerances are less severe, or disappear.
When stress is less, with a reduced production of catecholamines, the stress or fight or flight chemicals from the adrenals, we can often eat the poorly tolerated foods, 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 usually far from reality. I see anxiety and panic attacks increasingly as a simple catecholamine-driven reactions to mechanical or dietary triggering as well as psychological causes. So much anxiety is driven by mechanical causes, especially to the shoulder and spine, as well as foods the body sees as a threat.
The spine is a major factor in triggering TLRs, especially in migraine and fibromyalgia. This is obvious in people following MVAs, 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. This appears to be from local mechanical effects on the autonomic nervous system.
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) It appears that we can get whole body inflammation with mast cell activation in injury via slight alteration of the autonomic reflexes (the subject of our current research.)
The concept of Central Sensitization, where pain and altered sensory states may be due to synaptic and membrane excitability changes in the central nervous system and not necessarily due to processes in tissues has been around for over 20 years, and this helps to explain a lot of things such as arthritic pain, where for example eating lectins can produce typical arthritic pain in a hip or knee. Working out these food drivers, especially cow dairy, wheat, preservatives and lectins can provide remarkable reduction in pain (best seen in migratory/ variable arthritis.) I often find that after eg a shoulder or thoracic spine injury, pain starts in other areas, a knee, low back, neck etc, often followed by a cascade of seemingly unrelated problems including sleep disorder, “panic attacks,” IBS etc. Treatments are often directed to the back, knee, gut etc rather than the actual source of the problem.
The vascular compression syndromes, most prominently the thoracic outlet, popliteal, renal, and iliac vein compression syndromes are found in all POTS to varying degrees, and these are currently being investigated, although the evidence so far suggests it is compression of the autonomic nerves that we believe envelop these vessels that probably produce the main symptoms.
Compression at the distal end of the adductor canal in the thigh, about 12 cm up from the end of the femur, particularly when seated, is one that is becoming increasingly apparent, and ilioinguinal nerve entrapment has also been seen to produce significant symptoms especially in the legs. Ongoing research in other areas especially Fibromyalgia, Migraine and Hashimotos Disease, has found the same vascular compression syndromes in the majority of patients.
Other patterns are emerging. Many POTS patients describe symptoms starting after surgery, and various theories have attempted to explain this, but the most likely appears tom be from hyperextension of the neck during the de-intubation. This was described by Andrew Holman in 2008 (22). Similarly, non-epileptiform seizures have been identified with brainstem sensitivity driven through the C2 region of the cervical spine. The thoracic outlet compression does appear to affect this C2 region as well, making the pathways complex.
So disease activation appears to be by baroreceptor signalling, or local inflammatory responses to microemboli from the vein compression, or inflammatory chemicals eg IL-6, IL-8 and MCP-1 (monocyte chemotactic protein 1), found in sluggish blood (as seen in varicose veins.) (20) But it is the alteration in the autonomic nervous system response when compression is present(14) that is probably the primary factor in most patients I see, and why our research is targeting the autonomic activation with the various areas of compression as well as the neck and spine where there is evidence of injury (often occupational or posture) or activated trigger areas.
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, and from this comes realization of posture, and lifestyle change helps and this begins the path to recovery. 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. Many people’s symptoms improve with simple attention to their posture and how they use their phones, computers, and even backpacks and bags they carry.
Thoracic outlet syndrome
Thoracic outlet syndrome has been recognized for decades, at least from studies on soldiers in the 1940’s, but then largely forgotten. It was first identified as far as I can find in the 1940s in soldiers and labelled Costoclavicular syndrome- this review article (“The Costoclavicular Syndrome-a New Cause” by M de Silva.(19)) is well worth a read. Illig and Doyle(17) wrote: “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, the finding of recurring cardiac failure when lifting repetitively following a severe shoulder injury and damage to her thoracic outlet, and coupled with similar episodes of cardiomyopathy in others, provided the first major breakthrough in understanding the POTS pathogenesis.
Critically, the mechanism in this cardiomyopathy, as well as in POTS itself, appears to be similar to that seen in Takotsubo Cardiomyopathy, caused by a sudden release of catecholamines and other inflammatory chemicals, traditionally in response to a major stress such as the death of a partner. Increasingly it appears that baroreceptor signalling, most commonly from axillary or renal vein region (probably on the vessel walls so they are affected when veins compressed} causes TLR (Toll-Like Receptor) activation, then adrenal activation with release of catecholamines- a “Takotsubo response.” As in Takotsubo cardiomyopathy, where most people recover, but some don’t, it would appear to be dependent on release of IL-6 and TNF (and possibly IL-8 which is especially important if fibromyalgia co-exists).
Heart rate variability
Preliminary studies we conducted using static heart rate variability monitors to measure changes in autonomic tone in the vessels shows 2 distinct patterns, one obviously increased adrenalin, but in most POTS a reverse type of picture, probably from acetylcholine, and in the current mobile testing, both patterns are starting to emerge. Few controls have been tested as yet, so it is not known if these autonomic changes are “normal,” but I expect the activation to be exaggerated by other factors such as the “stretchy collagen” found in Ehlers-Danloss Syndrome and other people with hypermobility.
Acetylcholine has been implicated, as seen in research from Griffith University, in the cause of chronic fatigue, especially when there is a history of previous infectious mononucleosis. The HRV studies are starting to suggest this is a major factor in POTS and fibro fatigue.
In recent research from USA looking at people seen at emergency departments after syncope or sudden collapse, 20% have been found to have had pulmonary emboli. (11) Dyspnoea in patients with known chronic obstructive pulmonary disease (COPD) can be a clinical challenge due to the nonspecific nature of atypical presentations. Typical features of fever, productive cough, and wheezing on presentation support COPD exacerbation, while absence of such findings may warrant further evaluation for underlying aetiologies, including pulmonary embolism (PE). It is suspected that one in four patients with atypical COPD exacerbation may have PE as an underlying or concomitant cause of acute dyspnoea. (16)
The lungs should filter out any microscopic emboli from the compression areas. I strongly suspect many of the people with “asthma” not confirmed on formal lung function testing, sometimes presenting at emergency departments with chest pain and shortness of breath, have had microscopic cascades. Sometimes there is a positive D-Dimer test suggesting a pulmonary embolus, but with no sign of DVT or embolus in VQ lung scans, the usual tests, they are discharged. In all patients where we consider this a possibility, we have started regular lung function testing, and if appropriate, HS-CT lungs.
Mast cell Activation
Mast cell Activation is thought to be present in all POTS patients, and in early studies, in Fibromyalgia and Hashimotos Syndrome, and this in principal would sound to be the normal response in a body under threat. The work by Lawrence Afrin in Mast Cell Activation needs to be considered in combination with the changes that exist in these areas eg bladder when subjected to sympathetic or parasympathetic stimulation. 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)
But the theories become 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. There are many practitioners struggling to get on top of these problems, but seem to “fix” on one source. I have no doubt I have not worked out all the processes, but the improvement in the patients looking in these directions provides at least a light for people in whom the future has appeared very grim.
Looking at POTS causes, there are a number of apparent physiological changes in action. There is neural hypersensitization, adrenalin and acetylcholine release, microemboli, as well as inflammatory chemicals especially interleukins and TNF implicated. Yet the predisposition lies in our DNA.
All POTS have been shown to have one or more vascular compression syndromes, with Thoracic Outlet Vein Compression (TOSv) clinically producing the most dramatically- reproducible symptoms on examination, although the autonomic symptoms typical of POTS appear to be from compression of the autonomic nerves that we believe envelop the vessels. Whether it is direct autonomic compression or a secondary response in the brainstem is as yet unclear.
TOS (Costoclavicular syndrome) is known to cause recurrent pulmonary emboli in Paget-Schroetter Syndrome. Renal and iliac vein compression can be symptomatic. Popliteal vein compression is known to produce DVTs, pulmonary emboli and microemboli. Again, it appears to be from associated autonomic nervous system activation around these vessels that appear to be the most problematic.
These compression syndromes are common, and having one or more does not appear to produce symptoms in most people. There are no normal population studies. I can only suggest that there is a genetic component, and then trauma, sports and physical activity causing the important anatomical changes.
Clinically the underlying triggering of the threat receptors in POTS appears primarily to be from baro (pressure) receptor signalling, with the most common areas of origin the compression of the autonomic nerves that we believe envelop the axillary and subclavian vessels in the thoracic outlet as well as other compression areas notably the left renal vein, while other major areas include the upper cervical spine nerve afferents. One of the tasks ahead of us is to look at the way that the TOS affects the cervical afferents, as this lends a clue to the final sorting out of the pathogenesis..
Microembolic cascade and inflammatory cascade must be considered where unexplained shortness of breath and chest pain are present. When D-Dimer testing is positive with normal VQ Scanning, it is far more likely. Microemboli have been implicated in Idiopathic Pulmonary Hypertension, although researchers have been reticent to look at the quite obvious sources that have become evident through these studies.
The concept of microemboli causing lung “inflammation” starts to question many of the “asthma” diagnoses that have been made, unless definitely confirmed by formal lung function testing. In patients with microembolic risk, we have started yearly lung function testing to watch for change.
Things that “activate” POTS may not be the same as those that “drive” symptoms. The timeline of a patient’s health history usually provides the answers to both of these components.
DNA in POTS
DNA is so very important. The mechanical and other activators and drivers do not cause symptoms necessarily in other people, and it appears to be DNA polymorphisms that provide the difference.
- hEDS and hypermobility causing increased signalling from “increased stretchiness.”
- Methylation mutations (especially MTHFR) usually (100% in migraine), the 677 MTHFR mutation typically is associated with increased homocysteine, and probably affects collagen function as well as increased thrombotic risk.
- COMT frequently (= reduced ability to process catecholamines)
- Oxidative stress eNOS, SOD2. NO metabolism- associated with the development of FMS and pain sensitization
- IL mutations
- TRP mutations(threat receptors)- TRPM3 appears critical in NK immune cell function. TRPA1 is a key ion channel that detects oxidative stress and a range of endogenous and exogenous chemicals (smoke, solvents, cold air)
- Acetylcholine receptors (acetylcholine affects mitochondria causing fatigue).
FMS is characterized by widespread musculoskeletal pain, fatigue and cognitive difficulties. Central nervous system sensitization is a major component where various external stimuli eg infection, trauma and stress contribute to symptoms. The pain is neuropathic in nature, with changes in dermal unmyelinated nerve fibre bundles, while myelinated fibres are not affected.
Recent research has made some significant progress in the probable mechanism of this neuroinflammation, both central and peripheral. FMS has been “linked to inflammatory reactions and changes in the systemic levels of pro-inflammatory cytokines that modulate responses in the sympathetic nervous system and hypo-pituitary-adrenal axis” (21). Mendieta et al found higher levels of IL-6 and IL-8 than in healthy volunteers, and these 2 interleukins were 2 of the most constant inflammatory mediators in fibromyalgia, with levels corresponding to the severity of fibromyalgia symptoms, and that IL-6 and IL-8 could have additive effects in the continuous pain in fibromyalgia.
Inflammatory changes in glial cells in the brain has been reported, with the level of activation corresponding to the level of fatigue. Functional magnetic resonance (fMRI), demonstrate that activity is higher than normal in the areas of the brain that deal with pain, suggesting that pain signals are bombarding the brain or that the brain is abnormally processing pain signals from the body.
Increased levels of IL-6 and IL-8 in CSF and serum suggests symptoms are mediated by sympathetic activity rather than the previously assumed prostaglandin associated mechanism, and these levels appear to correlate to the severity of the FMS symptoms. It is thought these have an additive effect in the continuous pain of FMS. The finding of increased levels of these in varicose veins lends another potential driver from the vascular compression syndromes.
Elevated levels of Substance P have been found in the CSF of FMS, probably a secondary rather than primary phenomenon. Substance P is a chemical released when a painful stimulus is detected by your nerve cells. More specifically, substance P is involved with the pain threshold, which is the point at which a sensation becomes painful. Elevated levels of substance P could help explain why the pain threshold may be lowered in people with fibromyalgia.
Small fibre neuropathy has also been documented in PTSD, Hashimotos disease, Complex Pain Syndrome, and Restless Legs Syndrome, suggesting a similar pathogenesis.
DNA in Fibromyalgia
DNA mutations thus found:
- Ion channelopathy, (SCN9A, TRPV2, TRPV3): associated with development of FM and severity of symptoms
- DNA hypomethylation,
- Catecholaminergic – COMT mutations
- NO metabolism- associated with development of FMS and pain sensitivity (oxidative stress)
- Dopaminergic (DRD4)
- Serotinergic: anxiety-related traits, psychiatric symptoms, psychological distress
Overseas researchers have been mapping the DNA profiles in FMS. The ones I find most significant are the COMT (reduced capacity to metabolise catecholamines), MTHFR, IL-6, IL-8 (inflammatory cytokines) and eNOS and MnSOD/SOD2 (oxidative stress) mutations. The MTHFR mutation is so very common, and present in around 40% of the population, so it is no surprise that its long term problems are important in FMS.
Current research at Griffith University is exploring the array of Toll Receptor and Acetylcholine receptor polymorphisms that result in nerve hypersensitivity, altered channel ion channelling and cellular function that is involved in mast cell activation.
Activation can be from a wide range of problems -but underlying genetic and mechanical faults have to be present. Trauma especially to coccyx and shoulder and neck, parasites (especially blastocystis), infections, sustained stress (produces catecholamines as per Takotsubo) etc etc
Drivers can be mechanical (as below), food (when you eat food body sees as a threat it produces the same inflammatory responses), stress again, and even weather change itself. I think of collagen like a guitar string. When the weather changes, you have to re-tune it. But as the inflammatory responses are being controlled, the activation reduces and you improve. People with hypermobility have increased responses associated with the “increased stretchiness” of their collagen.
The spinal drivers below are currently the subject of HRV studies to confirm activation, as seen in static preliminary testing.
- Sacral injuries generally look to produce acetylcholine
- Upper cervical injuries are probably parasympathetic although neural sensitization symptoms appear most dominant
- Thoracic rotational injuries are usually adrenergic in nature
- Thoracic outlet- both sympathetic and parasympathetic
Migraine is about inflammation. Genetic information points to the involvement of transient receptor potential (TRP) channels in pain mechanism. TRPA1, an ion channel on the trigeminal (and most other sensory) nerves is the major oxidative threat sensor. It is activated by various irritants and agents releasing the pro-migraine peptide, calcitonin gene-related peptide through this nerve pathway. TRPA1 agonists release chemicals that cause vascular dilation.
Most migraine appears to be driven by cervical nerve root sensitivity. The cervical afferents of C1-3 are the reason we get increased sensitisation of the brainstem. The common pathway with the Trigeminal nerve will present as the head pain or facial pain plus associated symptoms of dizziness and nausea etc (C2/3). The head pain is a representation of the input from the cervical afferent nerves C1-3. This constant input will reduce the latency period (ie someone will get symptoms earlier than the normal person). This constant input then causes the brainstem to become sensitised and effectively “ready to go” with small input. This is why small variations (small C2 rotation perhaps from bad posture) or triggers will bring on large changes so quickly. The changes of this C2 rotation can very subtle and hard to find unless therapists are experienced in assessing these. (courtesy https://watsonheadache.com/
Successful management of migraine is really about “turning off” the processes that are driving the inflammation. In most people I see they are driven by the neck, sometimes thoracic outlet, although frequently it is very difficult to separate the TOS and C2 drivers, something that is part of our current research.
Certain foods that are “vasoactive” such as red wine, chocolate and aged cheese are well-known triggers. In women, hormonal changes at the times of menstruation can be a trigger. Sometimes it can be weather changes, or glare while driving, and the triggers can be obvious, but sometimes they can be very difficult to determine.
To complicate this is the research that implicates PFOs (Patent Foramen Ovale) as a cause of migraine “auras” in a number of adults (and it may be it is the same for kids), and again PFOs cause an inflammatory response, and when there is an aura (as described below) we may be looking at emboli (little TIAs or strokes) . There are not restricted to the brain as other vessels can be affected. The biggest problem I can see is the potential for dementia if this is not identified if present. Once the brain is damaged, it cannot repair itself. It does not mean though, that if you have auras you have a PFO and will get dementia. At present, the current thinking is that they are both common, and that a percentage of people with migraine who also have PFOs, which puts them in the risk for vascular disease, and should be assessed correctly. At present, as the knowledge is expanding we must review these periodically to see where the understanding of the condition has progressed and whether changed are required in management. We also believe now, that if we can eliminate the migraines, especially the auras, we probably need to do no further investigation at present.
The link between migraine and PFO was identified some years ago. Getting accurate trials has been very difficult to achieve, but when the patient selection criteria are correct, we are able to provide an 85% cure rate from migraine with the closure of the PFO. The other inflammatory processes discussed above also need to be addressed.
Around 20 to 25% of the population in general have foramen ovales that do not close at birth, but only a small percentage of patients with a PFO suffer with migraine and certainly not all migraine sufferers have a PFO. PFO is more common in migraine patients than in the general population- approximately 40 to 60% of people with migraine with auras have PFOs.
Approximately 40% of all strokes have no obvious cause, and this is more common in the under 60’s. In this group there is a higher percentage of PFO. The risk is higher if there is any medical condition that raises the pressure in the right side of the heart eg lung disease, pulmonary hypertension, pulmonary embolus, Obstructive Sleep Apnoea, DVT, cancer or any severe acute or chronic illness. The presence of an atrial septal aneurysm (mobile atrial septum) associated with a PFO or atrial septal defect also increases the risk of TIA/ stroke to 5% yearly.
Those who should be referred for assessment for a PFO include:
- The severe migraine with aura non responsive or intolerant to usual therapy.
- Blindness, hemiplegia or other significant neurological events would be a strong indicator for assessment (especially those whose employment is at risk or these events would place them or others in physical danger ie commercial pilots and divers).
- Anyone who we feel may have had a TIA (mini-stroke). Generally neurological symptoms lasting more than 20 mins in a migraine event could be TIA
- Migraine or anyone with unexplained changes in the brain MRI (or CT Spect)
- Migraine with aura who feel they have cognitive decline
- Severe migraine variants eg vestibular, abdominal
- The other masquerader is multiple sclerosis. If it’s obviously MS so be it but some just don’t behave clinically like it and the follow up MRIs don’t fit
- PFOs cannot be reliably diagnosed on an echocardiogram, the test most doctors use. They may need a Transcranial Doppler The actual PFOs are often very small, and may be only the size of a pinhead so there are no functional problems occurring in the heart.
- Looking at each of the contenders for pathogenesis.
- Takotsubo response where baroreceptor signalling, most commonly from axillary or renal vein region- probably on the nerve pathways so they are affected when veins compressed= TLR (Toll-Like Receptor) activation= adrenal activation= catecholamines (primarily adrenalin) = Takotsubo response. This would require the axillary and renal veins to have sufficient baroreceptors to elicit the responses. From renal artery denervation work that has been performed in resistant hypertension, this looks entirely possible that these areas are enveloped in a plexus of autonomic nerves.
Observed cardiomyopathy following trauma to a shoulder would implicate Takotsubo response as a major factor, (although microemboli potentially could cause the same response.) The increase in symptoms when patients are stressed would suggest that it is the catecholamines thus released as a major factor. Confirmed cardiomyopathy has been seen in this research to be part of the initial presentation of 3 patients, and many have symptoms of shortness of breath suggestive of this with normal echocardiograms. There are so many POTS patients with chest tightness and unexplained shortness of breath where this phenomenon would easily explain the cause.
POTS symptoms may persist in patients seemingly driven by TOSv following surgery to remove the first ribs, thus freeing the venous compression, but making the assumption that surgery can “fix” the problem is too simplistic. This then suggests that it is the hypersensitization of the autonomics in the region that produces the symptoms, and scarring of the nerves that envelop the vessels that causes the prolonged symptoms after surgery, and which would mean that the observed vein compression is only a guide to the presence of the compression producing the sensitization.
- Acetylcholine (Ach)– part of parasympathetic activation- Griffith University has found acetylcholine to be associated with chronic fatigue by affecting ion channels in mitochondria, which produce the energy in our cells. Impaired mitochondrial exchange – with calcium signalling at an intracellular level could be a common denominator in fatigue-related diseases that have some autoimmune aetiology. Fatigue seems to be a constant even when genetic implications vary from one form of autoimmune disease to another.
Research from Professor Sonya Marshall-Gradisnik and her team at Griffith University on the role of Ach and dysfunction cell receptors in TRPM3 in chronic fatigue probably explains much of the fatigue that incapacitates many POTS patients. The transient receptor potential melastatin subfamily 3 (TRPM3) is one of the most primitive receptors in the body, activated by a wide variety of agents, from bacteria and viruses to temperature and environmental factors such as perfumes. This diversity made it a logical suspect for a condition like CFS that has so many different triggers in different people.
TRPM3 is an ion channel, controlling the way calcium ions are transmitted between cells and carrying instructions in the process. Calcium is a major signalling molecule in the cell so any impairment is potentially disruptive…although there are some compensatory mechanisms.
Increased acetylcholine responds best to slow graded exercise, as Drs treating fibromyalgia have found, and POTS becomes worse when patients are confined to bed. I await with much anticipation the developing work from this group at Griffith University.
- Sensitization of neural pathways– Some areas in the spine are seen to provoke similar symptoms of autonomic dysfunction- eg direct pressure on C1/2/3, where there is sensitization of cervical nerve root afferents and brainstem (courtesy Dean Watson, https://watsonheadache.com/)
Similar sensitization occurs around T7 region in rotational activity (especially after seatbelt rotational injury or prolonged occupational activity), and sacrococcygeal joints (again usually a history of coccygeal injury,) although the autonomic response appears to be different to the thoracic spine injuries.
The sensitization appears to provoke autonomic symptoms with minor variations including posture. The responses can be quite dramatic and seemingly out of context with the activity. Craig Phillips from DMA Pilates Melbourne ( https://www.clinicalpilates.com/)
has provided evidence of the impact of rotational and other spinal injury on autonomic dysfunction.
- Microembolic processes– Compression of the popliteal and axillary/subclavian veins are known to produce emboli. In the extreme, sportspeople with TOS can get recurrent pulmonary emboli (Paget-Schroetters Syndrome.) Again, surgery to remove the first rib may remove the embolus risk but not the accompanying autonomic symptoms.
Having an elevated homocysteine (>9) increases coagulability, just as it is known to increase CV risk, although the mechanism is not known, and because of this, not used by most clinicians. It may be that this association of increased homocysteine reflecting increased cardiovascular risk may be by increased microembolic risk.
The microembolic risk is so important to sort out in migraine, especially if there are hyperintensities seen on brain MRI (I believe mandatory in migraine with aura and cognitive impairment.) 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, and 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 hyperintensities, 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. It is left to high sensitivity CTs of lungs and lung functions tests to provide the clues for this. Positive D-Dimer tests (for detecting pulmonary emboli) with a negative VQ scan for emboli are strongly suggestive of microembolic damage and should alert the clinician of the long term risks of this process.
- Interleukins, TNF and other inflammatory chemicals– . IL-6 (IL-8) and TNF release occurs in Takotsubo and is why the heart does not always return to normal after an “event.”
These are also found in “sluggish blood in varicose veins, so the vein compression may also contribute to the production of these, and as IL-6, IL-8 and TNF appear to be the primary factor in the multiple co-morbidities, especially fibromyalgia and Hashimotos Thyroiditis, they may be responsible for many symptoms.
Increased IL-8 has been found in increased concentrations in the CSF in FMS, and IL6 and IL-8 are now thought to mediate the inflammatory response in FMS, and to have implications in the typical small fibre neuropathy that is the major part of the pain processing that occurs.
Hypersensization in FMS is felt to be part of threat receptor hypersensitivity. There appears to be an array of TRP and Acetylcholine receptor polymorphisms that results in nerve hypersensitivity, altered calcium influx and cellular function – even immune responses.
Griffith Uni is exploring calcium channel (about 90 different ones) which then may influence monocytes differentiating into micro-glia to control brain blood flow. Glial cells are known as the “supporting cells” of the nervous system. The four main functions of glial cells are: to surround neurons and hold them in place, to supply nutrients and oxygen to neurons, to insulate one neuron from another, and to destroy and remove the carcasses of dead neurons.
The level of glial activation (inflammatory change) corresponds to the level of fatigue. Increased levels of IL-6 and IL-8 in CSF and serum suggests symptoms are mediated by sympathetic activity
We know they are involved in mast cell activation, which is thought to be present in all POTS patients.
Dynamic ultrasound demonstrates where some of the veins are compressed- axillary/subclavian, popliteal, iliac and renal. It is most likely that it is the triggering of the baroreceptors on these vessels that cause the problems, so even partial compression may cause symptoms. Thoracic outlet syndrome is increasingly being recognized clinically as a major cause of symptoms, but there are no scans at all available that will confirm or debunk the baroreceptor signalling theory. Only at present in clinical observation and heart rate variability can this be seen.
Preliminary static heart rate variability studies have confirmed 3 distinctly different patterns of autonomic response, and through 2019 we will be looking closely at the different activation types as a response to mechanical changes in the body, eg straightening legs to provoke a response from the popliteal veins, as we do not know yet whether the damage from them is microembolic or associated autonomic change. This I believe will be very important where renal vein compression is found, and where management options are very limited, so turning off other drivers will be paramount.
Driver fatigue and even panic attacks driving is very common in POTS. The activation appears to be through thoracic outlet compression, but increasingly I am seeing what I believe to be Adductor canal compression and ilioinguinal entrapment syndrome. Both of these should be easily managed with attention to seat position and driving position.
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. This appears to be from local mechanical effects on the autonomic nervous system. Orthopaedic research firmly targets the increasing use of mobile phones and computers for prolonged periods in the activation of these problems.
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. An easy clue to thoracic outlet syndrome is the frozen shoulder.
The overwhelming evidence from the POTS study showed the presence of one or more vascular compression syndromes in all patients. It seems most likely that these simply give us a clue to autonomic activation by compression of the nerves that envelop the vessels. 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. Adductor canal, ilioinguinal entrapment and femoral canal compression is an area being explored, but areas that are easily treated with postural change, eg use of a footrest when seated for any period.
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.
Ilioinguinal entrapment is a common finding, especially in people leaning forward at desks- once again computers the common thread.
During the study, it was trauma to the neck and shoulders that appeared to provoke the most significant symptoms in patients. Sometimes merely examining the thoracic outlet or having the popliteal veins scanned provoked the typical POTS symptoms. 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 I believe be aimed at removing the driving factors rather than looking for a medication to control symptoms. Of course if you cannot stand or arrhythmia is dangerous, or thyroid is destroyed and not functioning, you will need medication, or in vascular disease the statins Crestor and Lipitor do have anti-inflammatory effects in the vessels, reducing plaque, but more importantly the ARB blood pressure medications Atacand, Olmetec and Micardis have been shown to lengthen telomeres that bind our DNA, thus in reality repairing our DNA. The boundaries are blurring in management as well. Evolving research in nicotinamide (vitamin B3) opens yet another area that may assist the patients with hypermobility.
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 (especially effective is KIIKO style from Japan) 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 (and adductor canal?) compression can usually be managed by positional change 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. Currently we are exploring botox into the scalenes to reduce the impact on the thoracic outlet, despite the barriers placed in front as this has not been used before in POTS with venous compression.
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. The introduction of mobile Heart Rate Variability studies should provide the missing components to the sympathetic/parasympathetic activation, and working out the pathways of activation should enable the pathogenesis of POTS to be finally sorted out and appropriate management strategies put in place for all the variants we have found.
- Schmid, A., Nee,R., Coppieteres. Reappraising Entrapment Neuropathies-Mechanism, Diagnosis and Management. 2013. Manual Therapy 18 (449-457)
- Schmid,A., Hailey, L., Tampin,B. Entrapment Neuropathies: Challenging Common Beliefs with Novel Evidence. 2018. J Orthop Sports Phys Ther
- Afrin, L. Presentation,Diagnosis and Management of Mast Cell Activation Syndrome. 2013. Nova Science Publishers,Inc.
- Grosser, David: “Popliteal vein compression syndrome the main cause of DVT, unrecognised”, https://www.arteries-veins.com/single-post/2017/01/07/Popliteal-vein-compression-syndrome-the-MAIN-cause-of-DVT-unrecognised
- Mikita, n., Inaba, Y.,Yoshimasu, T., Kanazawa, N., Furukawa, F.: Mast Cells in Collagen Diseases. 2017. https://www.researchgate.net/publication/319359864_Mast_cells_in_collagen_diseases
- Bot, I., Shi, G., Kovanen, P.,Mast Cells as Effectors in Atherosclerosis. 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304944/
- Kamal Soliman; Steve Sturman; Prabodh K Sarkar; Atef Michael, “Postural Orthostatic Tachycardia Syndrome (POTS): A Diagnostic Dilemma,” Br J Cardiol. 2010;17(1):36-39.
- Krystel-Whittemore, M., Dileepan, K., Wood, J.G.. Mast Cell: A Multi-Functional Master Cell, 2016. https://www.frontiersin.org/articles/10.3389/fimmu.2015.00620/full
- Seneviratne,S.L., Maitland, A., Afrin A.: Mast Cell Disorders in Ehlers-Danlos Syndrome. 2017, American Journal of Medical Genetics Part C, 175C: 226- 236
- Milleret,Rene, “Popliteal vein entrapment: an unrecognised cause of failure in surgery for superficial venous insufficiency.”, Phlebolymphology. Vol 14 No 1 2007
- Prandoni P et al. Prevalence of pulmonary embolism among patients hospitalized for syncope. N Engl J Med 2016 Oct 20; 375:1524.
- Shibao,C.et al, Hyperadrenergic Postural Tachycardia Syndrome in Mast Cell Activation Disorders, Hypertension, 2005;45:385-390
- A K Agarwal, R Garg, A Ritch, and P Sarkar, “Postural orthostatic tachycardia syndrome,” Postgrad Med J. 2007 Jul; 83(981): 478–480.
- Exelby,G. Vascular Compression Syndromes in Postural Orthostatic Compression Syndrome (POTS)- A Preliminary Report. 2018. Academia.edu (since removed pending review)
- Kurlinsky,A., Rooke,T.: Nutcracker Phenomenon and Nutcracker Syndrome. Mayo Clin Proc, 2010.
- Durham, J., Machan, L.: Pelvic Congestion Syndrome. 2013. Semin Intervent Radiol
- Illig,k., Doyle, A.: A Comprehensive Review of Paget-Schroetter Syndrome, Journal of Vascular Surgery, Volume 51, Issue 6, June 2010,
- Sheil, W.C. Thoracic Outlet Syndrome (TOS)
- De Silva, M.,The costoclavicular syndrome: a ‘new cause’.Ann Rheum Dis. 1986 Nov; 45(11): 916–920. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1002019/
- Lattimer, C. R., et al. (2016). “Are Inflammatory Biomarkers Increased in Varicose Vein Blood?” Clinical & Applied Thrombosis/Hemostasis 22(7): 656-664.21. Mendieta, D., et al. IL-6 and IL-8 primarily mediate the inflammatory response in fibromyalgia patients. 2015. Journal of Neuroimmunology 290 (2016) 22-25. https://www.researchgate.net/publication/284722475_IL-8_and_IL-6_primarily_mediate_the_inflammatory_response_in_fibromyalgia_patients
- Holman, A. Positional Spinal Cord Compression and Fibromyalgia. 2008, Journal of Pain, Volume 20
Property of Dr Graham Exelby of Mermaid Central Medical Clinic The information contained in this document is not intended as medical advice. Please consult your medical professional.
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