Fibromyalgia Syndrome (Small Fibre Neuropathy- SFN)
Updated July 2019
A discussion document by Dr Graham Exelby, Mermaid Central Research
Fibromyalgia syndrome (FMS) is a common syndrome characterized by widespread musculoskeletal pain, sleep disorder, fatigue and cognitive difficulties. These symptoms appear unpredictable in their severity and timing until the “drivers” of the underlying inflammatory processes are identified. The symptoms of widespread pain, sensitivity to painful and non-painful stimulation, cognitive difficulties, and disturbed sleep are shared with other co-morbid syndromes eg Hashimotos Syndrome.
The pain of FMS often has a burning, aching quality, and varies in severity and position. The pain is neuropathic in nature, with changes in dermal unmyelinated nerve fibre bundles, while myelinated fibres are not affected (1)(2)(3). Diagnosis is largely by exclusion of other diseases eg SLE, although the patterns seen with the typical trigger point tenderness and other symptoms usually makes the diagnosis fairly easy. The pain is not fixed, and it varies with a wide range of factors such as activity, age, drugs, hormonal action, diet, illness, season, stress and even weather change.
Environmental and genetic factors predispose individuals to develop fibromyalgia. Symptoms usually start after a precipitating event such as injury or acute stress, although in some it is a cumulative series of traumas or “activators” which can include physical trauma, especially MVAs with neck and shoulder injuries, stress, parasites such as blastocystis hominis, moulds, infections, or prolonged postural or rotational causes often occupational in origin. The onset of menopause may precipitate FMS symptoms, as this is a time of autonomic instability.
Once the inflammatory process has been “activated”, symptoms are driven by “drivers” that may be different to the original activating problems. These may include rotational factors in the neck and thoracic spine, postural and other mechanical sources of inflammation from areas such as the thoracic outlet. Simple postural or mechanical factors may provoke symptoms in areas far-removed from a primary injury. Increasing food intolerance is commonly seen, with diet often impacting on symptoms, probably through increasing mast cell activation as the body attempts to defend itself against increasing threat.
Backryd et al found “evidence of both neuroinflammation (as assessed in CSF) and chronic systemic inflammation (as assessed in plasma.) They also replicated previous research concerning increased levels of IL-8 in both CSF and plasma. They concluded that “fibromyalgia seems to be characterized by objective biochemical alterations, and the lingering characterization of its mechanisms as essentially idiopathic or even psychogenic should be seen as definitely outdated.” (4)
The skin biopsy results with the neuropathy are very similar to that found in many other conditions, notably diabetic (and pre-diabetic) neuropathy, Sjogrens Syndrome, Lupus connective tissue disease, Sarcoidosis, Vitamin B12 deficiency, Coeliac disease, HIV, Amyloidosis, Paraproteinaemia, Alcohol abuse and Chemotherapy.
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 (5). 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 (6).
Many patients with FMS start with one or more trigger points described as myofascial points then progressively more are affected often at a time some distance from the original activating factor. With increasing hypersensitivity, driven by the “drivers” that differ in every person, scars, even freckles can be felt. Bodies become fatigued, yet unable to get to sleep with the activated fight or flight mechanism driven by catecholamines (primarily adrenaline).
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” (7). 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 (8). 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/ substance P- 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 (9) lends another potential driver from the vascular compression syndromes as many of the drivers include vascular compression areas, especially in the thoracic outlet.
Griffith University on the Gold Coast has established FMS to be part of the complexity of threat receptor hypersensitivity (see later on TLRs), and are working in an area called ion channellopathy. Other US researchers have found a very high incidence of non-myelinated small nerve fibre neuropathy (where there is significant damage to the small nerve endings especially in the skin) which explains the characteristic sensitivity to touch, and probably also explains the hypersensitivity in the vagus nerve which innervates the gut and heart producing symptoms of autonomic dysfunction (dysautonomia). Genetic researchers have made advances that help to explain why people confronted with the same activation processes may or may not develop POTS and fibromyalgia.
DNA in Fibromyalgia
DNA mutations thus found: (11) and Griffith University
- 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.
Turning off the Inflammation
Working through the problems leading to fibromyalgia, it 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.
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.
Working out the things that are triggering the innate immune system Toll-Like Receptors (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.
Drivers can be mechanical (as below), food (when you eat food body sees as a threat it produces the same inflammatory responses), stress again, hormonal fluctuation (especially at menopause when many FMS first become symptomatic), illness, moulds and other threats to the immune system 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 with neural sensitization symptoms most dominant
- Thoracic rotational injuries are usually adrenergic in nature, but early HRV studies suggest again both sympathetic and parasympathetic responses
- Thoracic outlet- both sympathetic and parasympathetic.
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.
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 (16) 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 (Postural Orthostatic Compression Syndrome) patients in our studies (over 100 at this point) to varying degrees, and these are currently being investigated. This research is part of a PH.D project in collaboration with University of Adelaide.
There are other compression areas- 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. Piriformis activation is very common, but so too is ilioinguinal, but it is difficult to establish if this is a primary problem associated for example with prolonged sitting, or secondary to flexion at T10/11/12 as has been documented by research physiotherapist Craig Phillips (DMA pilates Melbourne).
At this stage of the research, it is upper cervical and thoracic outlet compression that appears to be the most significant of the drivers established, although data has not yet been analysed. This combination is common after MVAs, where progressive dysfunction occurs, often affecting the gut, and appears to be a primary cause of the increasing anxiety and depression often seen, as well as the psychological impact of the fibromyalgia on their lives. Not surprisingly, as therapy to attend to the physical drivers proceeds, definite changes in psychological status has been found. The formal assessment of anxiety and depression during treatment phases of the FMS drivers has been commenced here in 2019.
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) (9). But it is the alteration in the autonomic nervous system response when compression is present 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, followed by fatigue that may last for days.
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.
Looking at each of the contenders for pathogenesis.
- Takotsubo Response
The mechanism in Takotsubo Cardiomyopathy, is 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, some don’t, as seen in the POTS research and 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). (15)
Clinically in POTS, the primary symptoms appear to be driven by this mechanism. Similarly this response is seen in many (perhaps all) fibromyalgia. In POTS (and FMS) 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, but as yet we have no formal anatomical data to confirm this. It will also require formal measurements of the interleukins, cytokines and other inflammatory responses with compression to confirm these clinical findings.
Observed cardiomyopathy following trauma to a shoulder in a POTS patient 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 and FMS patients with chest tightness and unexplained shortness of breath where this phenomenon would easily explain the cause, although there is a blurring of potential causes as there can be microembolic damage (as Paget-Schroetter Syndrome) and neural activated pain from the neurogenic thoracic outlet compression.
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.
Heart rate variability a way of measuring autonomic responses (ie Takotsubo response)
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 many others a reverse type of picture, probably from acetylcholine, and in the early mobile testing, both patterns are starting to emerge, with an initial “hit” of adrenaline then a parasympathetic response. Few controls have been tested, 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. The work in this has commenced in POTS, FMS and autoimmune diseases especially Hashimotos disease, as well as in normal volunteers.
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 work from Griffith would go a long way to explain the profound fatigue, and the HRV studies are starting to suggest this is in fact a major factor in POTS and fibro fatigue.
- 2. 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.
- 3. 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. It is interesting to look at the autonomic activation of these different areas. The upper cervical and coccygeal areas are parasympathetic, and from the top of the thoracic to the first couple of lumbar vertebrae are sympathetic.
All POTS patients 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. 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.
There have been POTS patients with symptoms from compression of the adductor canals in the legs where the deep veins in the leg are compressed on chair edges where the vein disappears into the deep muscle of the leg to emerge on the front of the leg.
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.
Prolonged sitting has been associated with increased cardiovascular risk. One study showed that riding in a car> 10 hrs/ week or sitting > 23 hrs/ week had 82% and 64% increased risk of dying from CV disease. Increased physical activity was associated with a reduced risk. Economy class syndrome describes the increased pulmonary embolus risk while travelling. While there are many factors in play, it seems to me that compression at the adductor canal may provide another aspect to managing this risk. While simple management is likely to be a footrest and awareness of when compression occurs, and adjusting seats to avoid symptoms, it does provide a potential clue to this emerging disease risk of modern society. Fatigue after prolonged computer use would appear to be of similar origin, either from the legs or thoracic outlet with constant mouse usage.
Compression of the popliteal and axillary/subclavian veins is 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 if the neurological symptoms have been prolonged as there is scarring that occurs around the nerves.
Having an elevated homocysteine (>9) increases coagulability, just as it is known to be associated with increased 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, while other researchers feel it reflects “pro-inflammatory 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 (PFO) 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. (ref: http://www.sharpecardiology.com.au/)
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, as you actually see the vessels themselves.
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. (14) 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.
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 appropriate 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.
- 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 (13) is well worth a read. Illig and Doyle (12) 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.) (12) 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.
- Mast cell Activation
Many people with FMS can describe a cascade of inflammatory processes, and when these are “time-lined” it appears that Mast Cell Activation has occurred, which not only appears to explain the cascade, but also provides an insight into the neuropathy and improving outcomes for the patients. 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.
“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. “ (10)
- 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 Hashimotos Thyroiditis, they may be responsible for many symptoms. Unfortunately it cannot be confirmed that these increased concentrations of interleukins are part of a systemic response or local to the affected areas.
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.
The TLR Receptors (Toll-like receptors) are the threat response receptors that are activated by threats to the body, from baro-receptor activation, stress, trauma, inflammation, food we are intolerant of etc. The TLR receptors (of which there are 11 in humans) affect different areas, eg TLR 4 seems to be involved in pain pathways. The success of the TCA’s, the old mainstay of medical treatment probably reflects their partial success is some people as they are effective in 2 of the human TLRs.
Changes in pain processes within the central nervous system lead to sensitization of pain pathways and its resultant clinical features, with lowering of pain threshold, and pain is often widespread. FMS is often reversible, but control of stress and other emotional factors are of critical importance. As mentioned, this is only part of dealing with the multiple triggers affecting the TLR receptors- these all need to be turned off to successfully treat FMS. The hypersensitivity makes pharmaceutical management very difficult as most sufferers are unable to tolerate medication at “normal” doses. There is often a hypersensitivity to chemicals, smells, sounds etc as well as barometric change.
FMS is common at all ages and in all societies, affecting females more than males. While most patients are middle-aged at presentation, it can be seen in children, teenagers and the elderly. Second only to osteoarthritis as the most common disorder seen by rheumatologists, it is recognised that FMS is an under-diagnosed and undertreated condition in general practice. FMS is poorly treated generally, I feel largely because of the constant pressure on time for over-worked GPs, and to a lesser extent in specialists who are probably more limited by the narrowness of their medical fields of expertise, but also a basic lack of knowledge especially while our educators lag behind in knowledge. FMS is a complex problem that requires a very detailed history to look at possible causes, and as consultations may take 90+ minutes, to include extensive family history to allow genetic modelling, it is likely to remain so.
FMS commonly occurs around the menopause when the autonomic nervous system is unstable. The symptoms of menopause especially the flushes and sweats are autonomic in nature, and reflect a dysfunction is autonomic stability; so controlling these is a vital part of FMS management. Menopausal dysautonomia may be the factor that tips someone with eg IBS and marital or work stress into full-blown FMS. It is not uncommon in children, although very difficult to diagnose accurately when they are very young. Fibromyalgia coexists with a number of chronic illnesses, ranging from inflammatory bowel disease and rheumatoid arthritis to osteoarthritis of the knee, and in this setting the clinical features of fibromyalgia will contribute to and often confuse the assessment of these disorders.
Turning off the threat receptors is vital to controlling the symptoms of FMS (SFN), whether it be physical or emotional stress, spine triggers, infections including the controversial dientamoeba and blastocystis and diet triggers which manifest as IBS. Simply using medication to control symptoms will not fix the problem. Taking narcotics to control the pain in reality increases the problem as morphine causes increased hypersensitivity to the already damaged nerves. Identification of young patients with localized symptoms is important to stop the progression to permanent damage.
Sleep disturbance has been identified as a major factor, and recent studies have reproduced FMS symptoms by inducing sleep deprivation in normal, although unfit subjects. EEG studies have shown a reduced amount of deep, non-dreaming, non-REM sleep with interruption by alpha waves. Increasing evidence shows that patients with FMS experience pain differently to the general population because of dysfunctional pain processing in the central nervous system. But the sleep disturbance is also characteristic of the heightened triggering of the threat receptors, the innate immune system activated and increased adrenalin output keeping the body on a “high alert” basis.
Food intolerance and its consequent problems appear to be present in almost all patients with FMS. Dealing with the intolerance is vital in controlling the fatigue and pain. In food intolerance, when you eat the relevant foods you are intolerant of, the innate immune system sees this as a threat and it produces a cytokine flux that affects the body in many potential ways including IBS, swallowing difficulties, fatigue, even bladder and potentially psychological effects. It is often difficult to work out which gut/ bladder symptom for example is driven by the autonomic activation or the food intolerance making the boundaries very blurred. Most people with food intolerances also have specific vitamin deficiencies associated with metabolic defects so these need to be sorted and treated, typical of the MTHFR mutation. These often include vitamin B12, vitamin D, Zinc, and Iodine. It seems to be at a metabolic level, but the mechanism is not yet understood.
Research from the allergist Dr David Freed implicates lectins as a major dietary factor.(16) This is particularly relevant if there is accompanying arthritis, especially rheumatoid arthritis, but the sensitivities can be to many different products. In others, it may be dairy, or wheat (or gluten), or sulphites among others.
I believe that the food industry is partly responsible for the increase in FMS, with heightened immune systems reacting to the tampering of our foods. Gluten is traditionally always the “fall-guy”, but in my experience, unless there is coeliac disease it is our modified wheat, or cow milk products or sulphites, salicylates, amines that is more commonly at fault. You can take someone brought up on a dairy farm on fresh milk, move them to the city, change the milk and produce symptoms. You may be intolerant of wheat in Australia, but ok in Europe.
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.
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.
Start with dealing with the obvious- the stress, the diet, obvious mechanical drivers which may be postural, and in TOS-driven symptoms avoid weight-lifting, working above the head, backpacks, heavy shoulder bags, prolonged computer work until scanning can determine the affected areas causing symptoms.
Where there is autonomic activation- sympathetic or parasympathetic, acupuncture provides an excellent starting point. Various types of acupuncture vary in effectiveness. At present we are using a Japanese style called “Kiiko” which directly targets the ANS. Good practitioners are able to pick whether a patient is in sympathetic or parasympathetic mode, and tailor treatment accordingly.
Exercise is paramount to good control of symptoms, and aerobic exercise such as walking has been unequivocally established as being vital to control of the FMS symptoms. It is known that exercise is possibly the only way to control acetylcholine.
It is with tertiary physiotherapy that long-term improvement usually starts to happen, although in some people just diet change may be sufficient to allow the body to deal with the other threats. There are a small number of physiotherapists adequately trained to identify and treat the mechanical and injured areas. This may lead to other exercise such as targeted pilates, yoga, Tai-Chi, and as the symptoms abate, exercise can be increased. Psychologists with specific knowledge of FMS are valuable in simply dealing with the psychological impact of the syndrome or in identifying repressed psychological trauma. There is a blurring of boundaries with PTSD, anxiety and depression with FMS and good management of these will reflect in better symptom control.
Duloxetine (Cymbalta) has provided valuable relief to many FMS patients, its relief thought to occur by lifting the nor-adrenaline in the nerve transmitters, thus controlling pain as well as accompanying anxiety and depression. But the benefit can be noted far earlier than expected when using this type of medication, so it seems likely that its success is through an as-yet unknown pathway. Interestingly the generic version of this product simply is not as effective in pain control. Generics are not the same as the original products, which provides a possible area of research into exactly what is improving the pain, by looking closely at the 2 products.
Frequently (and traditionally) the tricyclic (TCA) antidepressants are used with limited success. It is thought that these products turn off 2 of the TLRs. Unfortunately Duloxetine is not easy for FMS patients to take because of their hypersensitivity to medication, and TCA’s often cause tiredness. Morphine-like products should be avoided at all cost as these hypersensitize the already hypersensitive pathways, so a patient can end up dependent on drugs that really don’t work and are only increasing the problem. Low dose Naltrexone and Medicinal Marijuana are used by a number of patients, but as yet I cannot comment on safety or effectiveness.
FMS can be controlled. It takes time and patience. There is no magic “fix” but a progressive dissection of the underlying problems will allow each to be dealt with. The addition of activated Vitamin B12 (or variant) may be needed in the MTHFR mutations, Turmeric and Magnesium usually very helpful. Working out diet triggers is vital, and listening to your body for the sources of activation, much of which is mechanical, and may be well away from the areas originally injured. High-level acupuncture is also a very useful tool, especially in controlling the inflammatory/ autonomic pathways. Cymbalta while hard to use, if tolerated, usually controls the neuropathic pain. Tertiary physiotherapy -(Connect, DMA, Watson) are 3 types I use dependent on individual mechanical drivers. When there are flares, you must identify what caused this. An almost universal driver is barometric change, and there is always an increase in patients with flare-ups when the weather changes. For most people, with patience, there is a pathway out of fibromyalgia.
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