Fibromyalgia Syndrome  (Small Fibre Neuropathy- SFN)

 

Fibromyalgia syndrome (FMS) is a common yet generally poorly understood syndrome characterized by diffuse chronic pain accompanied by other symptoms such as fatigue, poor sleep and stiffness, often in the absence of any obvious disease or pathology. The essential features of FMS include widespread pain, fatigue, muscle stiffness, sleep disturbance and emotional distress. These symptoms are unpredictable in their severity and timing. The pain of FMS often has a burning, aching quality, and varies in severity and position. Muscles often ache after mild exercise. Multiple tender areas are essential for the diagnosis. 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.

 

Recent research has made some significant progress.   Dr Pete Smith, an immunologist on the Gold Coast has established FMS to be part of the complexity of threat receptor hypersensitivity (see later on TLRs), and he is 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 firmly established a much higher than normal association with the MTHFR gene mutations, which appears to be clinically the case as well.    This association is restricted by the inability at present to map all the MTHFR mutations (only 2 currently being tested in normal laboratories).

 

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.  This has led researchers to look at FMS in a different light.   In the past, and unfortunately even now in many areas, FMS has been considered a psychiatric problem.   In FMS/SFN there is a heightened sensitivity in the threat receptors, producing anxiety-like symptoms, and stress aggravates these.    It has been traditional to use TCAs (tricyclic antidepressants) but these drugs produce side effects, but may assist many people as they simply are sedating and also turn off 2 of the TLRs.

 

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. (2)   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. (3)

 

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.   While it may be increasing inflammatory responses associated with these compression syndromes, the release of a research in 2017 identifying the presence of previously undiscovered networks of interconnected fluid-filled compartments below the skin’s surface, lining the digestive tract, lungs and urinary systems, and surrounding arteries, veins and fascia between muscles may provide the missing part of this puzzle.

 

“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.” (1)

 

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.

 

FMS should in my opinion be considered a “Small Fibre Neuropathy”, no different than these other “more respectable” diagnoses without the stigma of psychiatric disease.   There is a blurring of boundaries when you investigate the FMS patients, so when you check the appropriate auto-immune studies, you can see a continuum that links SLE to Hashimotos Thyroiditis to Coeliac disease, to migraine,B12 dysfunction etc.   Sorting out FMS requires a careful long personal history and family history.

 

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 (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.   It is so widespread that many of the pathology “normals” that we use to assay for this mutation are incorrect, as these are “averages”.     This is especially seen in elevated homocysteine (over 9 is abnormal, not the quoted 15, as over 9 there is a significant vascular risk,) and also in Vitamin B12 levels.

 

The current use of PPIs to control reflux symptoms which is a very common Western society (dietary) problem has led to an increase in problems arising from B12 deficiency as the PPIs block B12 absorption.    No wonder researchers are looking at PPIs as possibly increasing dementia risk as increasing homocysteine is associated with increasing vascular risk, and now vitamin B12 is found to protect against dementia.    Unfortunately the researchers are missing the full picture.    So much hysteria has been raised over the MTHFR mutation- it causes impaired enzyme function in the important methylation processes in the body but it is so common, and implications so varied as there are 400 variations of genetic pattern that simply cannot be worked out completely at present.   In a simplified way, the primary mutations are in 677 and 1298, alleles, the former usually requiring B12 (or variant) to enhance function, but one size does not fit all.   Sometimes B12 alone is sufficient to reduce migraine frequency by half, and perhaps not surprisingly does improve dementia risk in may people as demonstrated in studies in 2010. Vitamin B12 appears to facilitate this enzyme activity, and this alone will often control developing vascular disease, migraine frequency, fatigue, and now early evidence of improvement in carpal tunnel and dupuyrtrens contracture.

 

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.    Looking at what causes the symptoms is time consuming but it allows control of the FMS/SFN symptoms.     Unfortunately for many people I see the neuropathic damage is already permanent so the best I can achieve is reduction or cessation of symptoms.    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 nerve endings.   Identification of young patients with localized symptoms is important to stop the progression to permanent damage.   Research in 2019 at Mermaid Central Research facility will be looking into the small fibre neuropathy that is the hallmark of FMS.

 

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.

 

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.

 

The vascular compression syndromes, most prominently the popliteal and thoracic outlet syndromes, and more recently observed, renal and iliac vein compression, are significant in the symptomatology in POTS  (Postural Orthostatic Tachycardia Syndrome), but it cannot yet be proven that they are the underlying cause, although addressing these does result in often dramatic reduction of symptoms.    In clinical settings, these trigger baroreceptors, mast cell activation and production of IL-6, cytokines and TNF.

 

Ongoing research in other areas especially Fibromyalgia, Migraine and Hashimotos Disease, has found the same vascular compression syndromes in the majority of patients.   Current investigation is looking at inflammatory responses when these vessels are compressed, and using heart rate variability studies, a change in the autonomic tone in arteries was observed.   This itself I think is insufficient and we need to work towards formally identifying the catecholamine and inflammatory chemical release that occurs when these veins are compressed.    It will be the sorting out of the IL-6 and cytokine production that will I am sure provide this missing information, but also a pathway to a diverse list of medical problems, especially non-alcoholic fatty liver (NASH), chronic pancreatitis (so perhaps diabetes), sleep apnoea, auto-immune disease and possibly hypertension.

Cytokines describe a diverse group of soluble proteinspeptides, or glycoproteins which act as hormonal regulators or signaling molecules at nano- to- picomolar concentrations and help in cell signaling.  They are regulators of host responses to infection, immune responses, inflammation, and trauma. Some of them are proinflammatory; these are necessary to initiate an inflammatory response necessary to recruit granulocytes, and later on, lymphocytes, to fight disease. Excessive inflammation, however, can result in certain diseases. Other cytokines are anti-inflammatory and serve to reduce inflammation and promote healing once the injury/infection/foreign body has been destroyed. (Source Wikipedia)

 

There are many other symptoms that may be present, that are part of a process called dysautonomia, such as difficulty swallowing, bladder and bowel abnormalities, and sometimes cognitive difficulties (Cognitive disorders are a category of disorders that primarily affect learning, memory, perception, and problem solving.).  Irritable bowel syndrome (IBS) is a particularly common accompanying disorder, as is Hashimotos thyroiditis, which I consider to be part of the same continuum.  There are no specific tests to confirm the diagnosis of Fibromyalgia Syndrome, although there are a number of diseases that need to be excluded before the diagnosis can be safely made, and many subtle auto-immune tests are elevated.  These co-morbidities are best explained as part of the Mast Cell Activation process.

 

Commonly, pain begins in an isolated region and is intermittent, yet it subsequently becomes more generalised and persistent in nature.     Variations in location and intensity from day to day are usual, and pain is often modulated by factors like weather, physical illness, physical activity (especially spinal) and psychological stress.   This is where the diagnoses should be made, when there are periods when there are no symptoms, before there is permanent damage.

 

While working with FMS, I have found there are multiple causes to the syndrome, and if all the causes can be addressed, then the disorder can be conquered and patients given their life back, depending on severity of damage.  There is a characteristic hypersensitivity, which is caused by a continued activation of the hypersensitized immune system (fight or flight mechanism through constant activation of threat receptors) by the various triggers in each person with FMS.   This same hypersensitivity is seen in autism.   This appears to be the genetic mutation in the COMT gene that occurs in both, where catecholamines, the fight and flight hormones are not metabolized in a normal way, leaving the body in a constant state of hyperalertness with its various symptoms.

 

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.   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.  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.    In IBS it is often triggered by stress or gut infections especially blastocystis or dientamoeba (which we can now treat thus reducing the gut inflammation.)   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.   Other modern causes are associated with posture, increasing use of computers and tablets, the general increase in stress, and exposure to increasing levels of chemicals and other toxins in our lives.

 

Chasing the causes of cytokine release, we find interesting causes, most dramatically PFOs in migraines, popliteal vein compression, and even sleep apnoea.   Closing a PFO often results in a loss of all other symptoms.    Just having a PFO does not mean it means to be closed, but certainly needs to be factored into the mix that drives FMS.   Popliteal vein compression puts people at a higher risk of DVT, and the cytokines released when they lie flat.  They will usually describe leg discomfort lying flat.    Easily controlled by side sleeping (often difficult in FMS where there is trochanteric pain) or a pillow under the knees.   This is also important when flying and if patients need surgery.    More information about this on David Grosser’s website http://www.arteries-veins.com/popliteal-vein-compression-syndrome.    Renal and iliac vein problems are discussed more fully in “Inflammation” on this website or in Mermaidcentralresearch.com.au.

 

Information on PFO and migraines at dysautonomia.com.au.    The work in thoracic outlet vein compression is ongoing as we look for non-surgical ways of dealing with this very important compression syndrome.

 

Current research revolves around the TLR Receptors (Toll-like receptors) as being the threat response receptors that are activated by threats to the body, whether this be trauma, inflammation, food we are intolerant of etc- this then provokes an immune response which activates the receptors.   There is responsible for the characteristic hypersensitivity seen in FMS.     The TLR receptors (of which there are 11 in humans) affect different areas, eg TLR 4 seems to be involved in pain pathways.

 

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.   This appears to be part of the Mast Cell Activation that occurs as the body attempts to deal with stresses placed upon it.

 

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 but also a basic lack of knowledge especially while our educators lag behind in knowledge.    And as a decent history to look at possible causes takes 90+ minutes, to include extensive family history to allow genetic modeling, 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.

 

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 it probably turns off the TLRs, or controlling the prostaglandin released by activated mast cells, or perhaps the inflammatory chemicals from compressed vessels and nerves.   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.      Where pain is difficult to control, the availability of a new neuropathic pain agent, Lyrica occasionally is useful.     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.

 

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. There are a small number of physiotherapists trained in “targeted pilates” where the specific injured areas are isolated, and specific exercises implemented.    This may lead to other exercise such as yoga, Tai-Chi, and as the symptoms abate, exercise can be increased.     Psychologists with specific knowledge of FMS is valuable in simply dealing with the psychological impact of the syndrome or in identifying repressed psychological trauma.

 

FMS/SFN 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) is usually needed, Turmeric very helpful, Magnesium usually helpful, working out diet triggers vital, and appropriate spine assessment –usually DMR, Connect Therapy (especially when thoracic compression is a component) Feldenkrais or Dean Watson therapists essential.   High level acupuncture is also a very useful tool, especially in controlling the inflammatory pathways.  Cymbalta while hard to use, if tolerated, usually controls the neuropathic pain.    When there are flares, you must identify what caused this.    Common is barometric change, and there is always an increase in patients with flare-ups when the weather changes.

References:

 

  1. Afrin, L. Presentation,Diagnosis and Management of Mast Cell Activation Syndrome. 2013. Nova Science Publishers,Inc.

 

  1. Schmid, A., Nee,R., Coppieteres. Reappraising Entrapment Neuropathies-Mechanism, Diagnosis and Management. 2013.  Manual Therapy 18 (449-457)

 

  1. Schmit,A., Hailey, L., Tampin,B. Entrapment Neuropathies: Challenging Common Beliefs with Novel Evidence. 2018. J Orthop Sports Phys Ther