Dr Graham Exelby February 2024
Introduction
This article on management is based extensively on hundreds of face to face consultations in our clinic. Much is based on previous research from Griffith University in CFS, from research in MS over a decade ago and from the Gulf War Syndrome, and from the DNA research by Dr Valerio Vittoni in POTS and Long Covid, from Kjetil Larsen in Thoracic Outlet Syndrome and Intracranial Hypertension, but putting it together is the result of looking closely at each patient. There is new research from 2023 and 2024 providing the source of areas such as the mechanisms in coathanger pain, post-exertional malaise (PEM), and the association with CFS and Intracranial Hypertension. It is meant to complement the article: Fibromyalgia Syndrome and the Linking with POTS and Chronic Fatigue Syndrome.(42)
From our research we have formulated hypotheses regarding areas such as cardiac preload dysfunction to cause the unexplained shortness of breath so frequently seen. This preload dysfunction increasingly appears to be associated with Azygous dysfunction, and subject to close scrutiny, but limited by difficulties in radiology.
Most of the vascular compression syndromes can be demonstrated on Spectral CT head to pelvic angiography with venography, perfected again at Mermaid Beach, but all these MRIs and CTs are limited by being done supine, and many of the “mechanical and hydraulic drivers” can only be proven on dynamic ultrasounds, and these are limited by the skillset of the sonographers.
From these we can provide assistance to management of FMS and its co-morbidities.
What is Fibromyalgia?
Fibromyalgia Syndrome (FMS) is a chronic disorder that causes pain and tenderness throughout the body, as well as fatigue and sleep disorder. The pain of fibromyalgia is typically diffuse, migratory (moves from one joint to another) and may involves both muscles (myalgia) and joints (arthralgia). It affects both sides of the body, and above and below the waist. Typically this can be associated with increased skin sensitivity even to touch.
FMS commonly is first recognized around the menopause when the autonomic nervous system is unstable, although there are usually clues that may date back decades into infancy. The symptoms of menopause especially the flushes and sweats reflect a dysfunction in autonomic stability, and menopausal dysautonomia may be the final factor that tips someone with pre-existing problems into a recognisable diagnosis.
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, and in this setting the clinical features of fibromyalgia will contribute to and often confuse the assessment of these disorders. There are so many cross-overs, eg patients especially children may demonstrate the same sensitization that characterizes FMS sensitization with issues with sound, light tolerance. The work from Hulens (11) and Bragee (10) demonstrated the cross over with Intracranial Hypertension, Chronic fatigue, and Fibromyalgia. Tilt tests in CFS in small studies by Raj et al (12) confirmed POTS and CFS to have similar causes. Research at our clinic confirm that whatever the ‘activation” many of the same physical drivers are present. This may be seen in the recurring symptoms of Intracranial Hypertension.
Overlapping Conditions
Attempts to reduce fibromyalgia to one or 2 causes or depend simply on anti-depressants, anti-neuropathic medication, or on management of dysfunctional mast cells for example, is usually fraught with failure as it is a summation of multiple metabolic, psychological, genetic, infective, traumatic, mechanical, dietary and inflammatory factors.
At a clinical level, fibromyalgia is much more than widespread pain. It overlaps substantially with other syndromes. With the increasing awareness of the underlying DNA mutations in FMS, there is an increasing ability to understand these associations.
Figure 1. Overlapping Conditions
Table 1: Established Co-morbidities and Possible Underlying Causes-Table based on clinic assessments
Chronic Fatigue Syndrome -see Table 3
Irritable Bowel Syndrome
TLR4 / cytokine /microglial activation
Mast cell activation
autonomic dysfunction including Intra-abdominal Compression Syndromes
Chronic pelvic pain syndrome/primary dysmenorrhoea
TLR4 / cytokine /microglial activation (please note endometriosis has been confirmed to be associated with TLR4 signalling.)(41)
Mast cell activation
Pelvic congestion syndrome
Intra-abdominal compression syndromes (especially May-Thurner and Nutcracker Syndromes with probable effects from paravertebral and azygous vein dysfunction)
Temporomandibular joint pain
Upper cervical dysfunction
Post-Traumatic Stress Disorder (PTSD)
Multiple chemical sensitivity
TLR4 / cytokine /microglial activation
Mast cell activation
Periodic limb movement disorder/ restless legs syndrome
Central sensitization (an aspect of increased spinal cord excitability related to impaired modulation by dopaminergic pathways) (13)
Interstitial cystitis
TLR4 / cytokine /microglial activation
Intra-abdominal compression syndromes
Mast cell activation
Food intolerance
Migraine /tension headaches
Upper cervical dysfunction (especially C2/3)
Impaired glymphatic flow and activated microglia and astrocytes (14)
Central sensitization
Intracranial Hypertension
CSF flow obstruction (including lymphatics head and neck)
Intracranial venous obstruction (see below)
Postural Orthostatic Tachycardia Syndrome (POTS)
See Assembling the Pieces of POTS (43)
Figure 2: Trigger Points in Fibromyalgia
Source: Torborg,L. Understanding myofascial pain syndrome and fibromyalgia. 2017. Mayo Clinic. https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-q-and-a-understanding-myofascial-pain-syndrome-and-fibromyalgia/
Tackling Fibromyalgia
Initially I believe the diagnosis of FMS needs to be confirmed, as it is often given as a “throw-away” diagnosis. Mimics include SLE and PMR, and so important that these be excluded. Hashimotos, CFS and migraine again turn up with regular monotony. Increasing complement dysfunction is occurring, noticed in Long Covid investigation. In clinic we use HS-CRP and in many, there is a low complement C3 accompanying a suppressed HS-CRP.(30) The implications are uncertain at present, but it may provide a clue to those with TLR2 triggered/astrocyte/glutamate dysfunction. As CRP and HS-CRP are primary investigations used to measure inflammatory load, these may slip under the radar.
Abnormal liver function, homocysteine and elevated thyroid antibodies are commonly seen. Pulmonary microemboli are not uncommon, and D-Dimer should be checked, especially when there is periodic chest pain. In the Covid-related patients, amyloid may be involved in the fibrin tangles of these clots, and from the DNA assessments, PEMT mutations are likely to be present. PEMT and other neurodegenerative mutations are commonly found. Mostly of these have no biomarkers and clues in family history of neurodegenerative and liver disease may be seen and can only be seen in DNA.- DNA Mutations in POTS and Long Covid (32)
Heart rate variability
Heart rate variability is a very valuable tool to assess autonomic dysfunction. This is not easy to get without a HRV monitor, but can be seen in some Holter Monitors. -detailed in Heart Rate Variability (44)
Jason Moore (38) describes
“Parasympathetic regulation lowers your heart rate from the intrinsic level, giving more room for variability between successive heartbeats.
Parasympathetic regulation causes almost immediate changes that affect only a few beats at a time, after which heart rate returns towards the intrinsic rate.
Sympathetic regulation elevates your heart rate from the intrinsic level, and there is less room for variability between successive heartbeats. Sympathetic regulation affects several consecutive heart beats.
Both parasympathetic and sympathetic branches of the nervous system are mediated by cortical-subcortical pathways which involve the prefrontal cortex, the anterior cingulate cortex, the insula, the hypothalamus, and the brainstem. The prefrontal cortex regulates and tonically inhibits activity in limbic structures which act to suppress parasympathetic activity and activate sympathetic circuits–
Variation in the output of these two branches of the autonomic system produces heart rate variability (HRV), a measure of autonomic nervous functioning. Therefore, activation of the prefrontal cortex results in change to HRV, which can be thought of as a measure of the aggregate effect of activity in a complex brain network, regulated top-down by the prefrontal cortex.”(38)
Figure 3. Mildly sympathetic dominance over 24 hr
Figure 4: Marked sympathetic dominance with SDNN suppression.
Figure 5: Chaotic pattern from a POTS patient showing oscillations that can be often seen.
This pattern is from a patient with an Internal Jugular Vein Obstruction at the venous angle, where we believe the IJV dilatation has cause increased pressure in the carotid sheath triggering the carotid baroreceptors, setting up a pattern of oscillations as described by Geddes et al (34). Similar patterns may be seen in intra-abdominal compression syndromes affecting the coeliac plexus and vagus.
Source: QML Pathology Holter Monitor (page 2)
Working out the things that are triggering the immune system -the role of activation of the body’s threat receptors (Toll-Like Receptors) and immune response via Mast Cells, affecting microglial and astrocyte function in the nervous system and the symptoms this causes, is critical to understanding and controlling fibromyalgia and its comorbidities. But like Pandora’s Box, when you open this it can be very complicated with the multiple genetic and environmental factors that predispose people to FMS and various drivers to work out. But each one you do control can improve the quality of life in someone with this immeasurably.
For most patients with FMS a solid history provides a path to the “perfect storm” with multiple findings with clues that may be found from birth, often with progressive symptoms until the main trigger which may be infective (especially SARS-C-2), parasites, trauma (especially to the spine), or sustained stress as well as others. 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, falls onto the neck or coccyx, stress, parasites such as pro-inflammatory subtypes of 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. Even the increasing breast weight of menopause can be problematic, adding to the dysfunctional autonomic changes.
Ehlers-Danlos Syndrome is a very significant factor both in increased predisposition and management. The association of EDS and mast cell activation has been well established. EDS has also shown a significant similarity with increased incidence of immune-related diseases eg asthma, neuropathy and arthritis.(35)
FMS symptoms often disappear when stress is not present, so many people are considered to have only psychological problems, which is usually far from reality. Unexplained anxiety and panic attacks driven by catecholamine-driven reactions to mechanical or dietary triggering as well as psychological causes. COMT mutations found in all FMS, with the impaired capacity to deal with catecholamines produced mechanically or from psychological stress are not processed efficiently. Often there are symptoms from birth and manifest in sleep disorder.
So much “anxiety” is driven by mechanical causes, especially to the shoulder and spine, as well as foods the body sees as a threat. So many patients with underlying intra-abdominal vascular compression syndromes especially Median Arcuate Ligament Syndrome and Superior Mesenteric Artery Syndrome, both common in POTS and FMS, are labelled as “eating disorders,” a label that is hard to shake even when the others are confirmed. Even as infants, mothers may be blamed for feeding difficulties when there is an underlying disorder.
When there are flares, you should attempt to identify what caused this. A common (? Universal) driver is barometric change, and there is always an increase in patients with flare-ups when the weather changes. When severe, driving up a mountain may trigger symptoms, usually tachycardia. A strong suspicion of thoracic outlet syndrome may be symptoms washing hair. Rotation of the thoracic spine may produce tachycardia in 1 direction.
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. Working out diet triggers is vital, and listening to body “signals” for the sources of activation, much of which is mechanical, and may be well away from the areas originally injured. For most people, with patience, there is a pathway out of fibromyalgia.
Dissecting symptoms:
It is difficult but important to dissect co-morbidities and symptoms themselves. Start with dealing with the obvious such as trauma, PTSD, food intolerance, fatigue, central sensitization, brain fog, and head pressure.
Coat hanger pain
“Coat hanger pain” is seen frequently in patients with dysautonomia, especially POTS, as well as fibromyalgia and CFS. Humm et al (19) describes the typical ache usually began with standing or sitting, as discomfort and pain in the neck and shoulder, and research suggests this could result from reduced blood flow and oxygen delivery to the muscles in the affected areas. They showed that muscle membranes in patients with orthostatic hypotension become progressively depolarized during standing, which they felt was most likely the result of muscle ischaemia, related to the drop in perfusion pressure caused by orthostatic hypotension.
Brainstem Hypoperfusion
Hypoperfusion in the brainstem is a very common finding in brain SPECT scans in CFS. Wirth et al (20) described reduced blood flow causing neurological symptoms including impaired cognitive function or “brain fog.” Increased intracranial pressure, as proposed by Hulens (11) and Bragee (10) has also been frequently observed compounding problems (actual rates pending database analysis.)
The brainstem hypoperfusion seen in CFS Spect scans is believed to be part of the same process of hypoperfusion and mitochondrial dysfunction that underpins the coat hanger pain of FMS,(49) although an emergent hypothesis of glutamate/astrocyte dysfunction by Guedl (21)(22) in Long Covid provides a possible explanation for some impaired glymphatic function through impairment of the paravascular space function and potential effects on symptoms such as fatigue, brain fog and head pressure.
This astrocyte association becomes very relevant in FMS where glutamate dysfunction has already been recognized, and with this the impairment of glymphatic function.
Wirth et al (20) noted that reduced cerebral blood flow in CFS can lead to a range of neurological symptoms, including psychomotor slowing and impaired cognitive function in CFS. This hypoperfusion can impact both the global and local regulation of blood flow in the brain. They also reported an increase in intracranial pressure has been observed in ME/CFS patients.
In the severe CFS, a reduction in blood flow from lying to sitting was 24.5%. As a possible explanation for the orthostatic intolerance and the decrease in cerebral blood flow they proposed the presence of both a strong vasoconstrictor effect mediated by an elevated sympathetic tone and weakened vasodilator influences. Covid-19 seriously affects the endothelium and there is evidence of chronic endothelial dysfunction in the post-Covid-syndrome similar to that in ME/CFS.(52)
Similarly, Wirth et al (20) reported muscle mitochondrial dysfunction, as evidenced by higher levels of pyruvate and lower levels of ATP and phosphocreatine in muscles, suggesting an impairment in muscle energy metabolism, which is also observed in ME/CFS, indicating a likely overlap in the pathophysiological mechanisms of these conditions.
Long Covid research by Appleman et al, (17) has also shown post-exertional malaise (PEM), with associated fatigue, pain and local and systemic metabolic disturbances, severe exercise-induced myopathy and tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID. The impaired recovery from venous obstruction suggests vasoconstriction from noradrenergic activity as we have been finding. The finding of amyloid in Long Covid is very suspicious of underlying DNA mutations, especially in PEMT where there are no biomarkers. As far as I am aware there is no evidence of amyloid in skeletal muscle in other causes of FMS other than Covid.
Brain fog
In POTS patients (when brain fog was present) after cognitive challenge, Wells, Lau et al (15) found the middle cerebral artery flow was found to be reduced using transcranial doppler flow studies. The cause of this may be linked to the postural hydraulic and mechanical changes of neck and arm positioning and head-forward positioning rather than the cognitive challenge. Irrespective of whether this is from pure cognitive challenge, or from mechanical factors, it implies vasoconstriction from the locus coeruleus, yet to be proven.
When the central sensitization is severe (as seen in all POTS) it is a strong theoretical observation that a head-forward position of the subjects may have been associated by Internal Jugular Vein dilatation and baroreflex sympathetic signalling, with the possible increase in vertebral venous pressure and lymphatic adrenergic signalling from the vessel walls. Lymphatic flow is slow and would be unlikely to cause any backpressure in the cranial lymphatics itself, and is unlikely to provoke the symptoms described in these studies. This could be compounded in neck flexion and rotation in IJV obstruction as seen in our preliminary studies.
Van Campen, Rowe and Visser (24) demonstrated reduced middle cerebral artery flow in tilt testing in Long Covid patients, improving over time, reflecting improving autonomic dysfunction over time as sensitization from Covid settles. They also found cerebral blood flow and cardiac index reductions (Preload dysfunction) during tilt were more severely impaired than in many patients with CFS.
Sonkaya et al (25) found an increase in basal cerebral blood velocity and a decrease in vasomotor reactivity rates in patients with Covid-19 which they considered as an indicator of dysfunction of cerebral haemodynamics in the central nervous system.
They found no significant differences in ME/CFS symptom prevalence between the long-haul COVID-19 patients and the ME/CFS patients. All long-haul COVID-19 patients tested developed POTS during tilt. Cerebral blood flow and cardiac index reductions during tilt were more severely impaired than in many patients with ME/CFS. The finding of early-onset orthostatic intolerance symptoms, and the high pre-illness physical activity level of the long-haul COVID-19 patients, makes it unlikely that POTS in this group is due to deconditioning, the prevailing medical opinion, and inherently incorrect, and confirmed by van Campen et al in CFS.(27)
This paper confirmed the importance of autonomic dysfunction and cardiac preload dysfunction in POTS, Long Covid, CFS, and challenged vertebral artery impaired flow as a potential cause of the brainstem hypoperfusion. FMS patients frequently are found to have the same symptoms.
Table 2: Potential Sources of Brain Fog-Table based on clinic assessments
Brainstem hypoperfusion, especially in chronic fatigue (hypoperfusion, mitochondrial dysfunction, muscle depolarization and move to amino acid metabolism if prolonged)
Impaired glymphatic flow (especially with symptoms of head and/or pressure), as noted by Hulens (11) and Bragee (10) and consistent with clinic findings. Pressure head/ eyes when lying is usually CSF flow disruption, especially if accompanied by pulse synchronous tinnitus and brain fog
Upper cervical dysfunction- C0/1 and if associated with Jugular Outlet Syndrome obstruction at the stylohoid. Vagus and other cranial nerves may be affected.
Cerebral artery hypoperfusion- as confirmed by Wells, Lau et al (15) in POTS.
Endotheiliitis from venous congestion, as seen in unpublished study on SPECT scans brain. These may or may not be associated with brainstem hypoperfusion as no tilt/NASA lean testing accompanied these scan, but did differentiate between subtypes.
Inflammation as seen with reduced symptoms from diet change, histamine blockade, Low dose naltrexone
Microembolic, a risk especially with COVID thromboembolic change (probably PEMT mutation where no biomarker exists, and COVID carries the risk of accompanying amyloid involvement in the fibrin) and migraine with prolonged aura, and presence of a PFO.
APO E4, LPa, PEMT and other neurodegenerative mutations. APO E4 also affects liver function and risk of arterial damage
Variability in brain fog may reflect changing intracranial pressure, both CSF and venous.
Table 3: Potential sources of Chronic Fatigue- Table based on clinic assessments
Hypoperfusion with mitochondrial dysfunction /oxidative stress (CFS and coathanger pain with progressive muscle depolarization)
Astrocyte /glymphatic dysfunction (TLR2-driven or crosstalk with microglia)
Neurotransmitter dysfunction -Dopamine/serotonin/glutamate pathways
Intracranial pressure abnormality with HPA axis dysfunction
Metabolic pathway abnormality/ DNA mutations /Dietary
Small fibre neuropathy
Autonomic instability eg POTS, dysautonomia, orthostatic hypotension
Impaired cardiac function
Cardiac preload failure
Locus coeruleus
Aberrant azygous anatomy/ sympathetic activation (currently being investigated)
Sensitization mechanically
Secondary to Thoracic /Lymphatic duct obstruction
Associated with Intra-abdominal vascular dysfunction
COVID
Reactivation of EBV and other viruses
Cardiac damage- pericarditis, myocarditis, reduced EF%
Lung and other organ damage-embolic, inflammatory, malignant
Head/ eye pressure:
The importance of the work by Bragee (10) and Hulens (11) makes these observations so very important. COVID does produce problems such as thromboses in the dural sinuses of the brain, and MRI venography is usually needed in particular to look for signs of Intracranial Hypertension, dural sinus dysfunction, chiari formation, MRI hyperintensities (which are so commonly missed or misinterpreted.)
Pressure head/ eyes when lying is usually CSF flow disruption, especially if accompanied by pulse synchronous tinnitus and brain fog
Pressure sitting/standing usually venous congestion in head and neck. Common culprits are the Thoracic outlet syndrome, Jugular Outlet Syndrome, and probably most importantly Internal Jugular Vein Obstruction at the venous angle
Intra-abdominal vascular compression, eg Nutcracker and May-Thurner Syndromes simply put increased blood flow into the pelvis. These have been shown by Scholbach (16) to increase CSF pressure. Blood has to go somewhere when normal channels are not functioning. The Azygous system provides a “back-up” to venous congestion, but there are a number of anatomical variants where the system is incomplete. We are currently researching dysfunctional Azygous function as the primary cause of the cardiac preload dysfunction that causes the unexplained shortness of breath typical of POTS and most FMS.
Post-exertional malaise:
The work by Appelman et al (17) provides most of the information needed to comprehend what is happening.
Appelman describes a conversion to amino acid metabolism after the hypoperfusion, mitochondrial dysfunction and muscular depolarization. This is currently an area of research as pre and post malaise activation are showing significant metabolic changes.
Vasoconstriction/ hypoperfusion
Systemic metabolic changes
Mitochondrial dysfunction
Muscle damage (myopathy)
Tissue infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID.( Appleman et al)
Amyloid probably not involved normally but Covid-related suspicious of underlying DNA mutations eg PEMT, ? COMT
Impaired recovery from venous obstruction suggests vasoconstriction from noradrenergic activity
Generalized pain:
While the coathanger pain can be localized, the generalized pain is more complex. It is usually accompanied by skin sensitivity-often patients cannot bare to be touched.
Hypersensization in fibromyalgia, where the characteristic pain is now known to be small fibre neuropathy had been felt to be part of threat receptor hypersensitivity as there appears to be an array of TRP and Acetylcholine receptor polymorphisms that results in nerve hypersensitivity, altered calcium influx and cellular function and even immune responses. As a consequence of the aberrant mast cell activity, it now appears that the sensitization is caused by the microglial sensitization. A subtle difference, but important in consequence as it enables an approach based on managing the aberrant mast cell responses.
Griffith University Gold Coast has been exploring calcium ion channels which then may influence monocytes differentiating into microglia to control brain blood flow. 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 autonomic activity.
A number of abnormalities in pain processing have been demonstrated in fibromyalgia. Among them are the following:
Excess excitatory (pronociceptive) neurotransmitters (eg, substance P, glutamate levels in the insula)
Low levels of inhibitory neurotransmitters (eg, serotonin and noradrenalin) in descending antinociceptive pathways in the spinal cord
Maintained enhancement of temporal summation of second pain
Altered endogenous opioid analgesic activity in several brain regions known to play a role in pain modulation
Dopamine dysregulation (3)
The biochemical changes seen in the CNS, the low levels of serotonin, the four-fold increase in nerve growth factor, and the elevated levels of substance P all lead to a whole-body hypersensitivity to pain and suggest that fibromyalgia is a condition of central sensitization and abnormal central processing of nociceptive pain input.
Central sensitization can be tracked to TLR4 activation, then via mast cells, more cytokines, and microglial activation. This complicated by cross-talk between microglia, astrocyte and mast cells. Trauma, eg neck and coccyx appear to activate the mast cells even before the threat receptors.(18) You often have to decide which one to initiate treatment on.
Fibromyalgia “Drivers”
Attempts to reduce fibromyalgia to one or 2 causes or depend simply on anti-depressants, anti-neuropathic medication, or on management of dysfunctional mast cells for example, is usually fraught with failure as it is a summation of multiple metabolic, psychological, genetic, infective, traumatic, mechanical, dietary and inflammatory factors.
Once activated, symptoms continue to be driven through “drivers.” Drivers can be mechanical, dietary, stress, 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 when FMS is in full flight.
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. The rotational -triggered symptoms have long been assumed to be from nerve sensitization in the spine, especially at T4 and T8 levels. These 2 points increasingly look to be associated with dysfunction in the Azygous system, and the close association with the thoracic and right lymphatic ducts, and the sympathetic pathways in these vessels, which may provide a link to cardiac preload dysfunction as a cause of the unexplained shortness of breath in many patients.
It is expected there will be an increase in autonomic-related symptoms over future years as people become more dependent on their computers and tablets, while their posture is not attended to. Indeed, phone and computer use affect cervical spine function, and with this, alterations to cerebral craniovascular perfusion.
Working out food drivers, especially cow dairy, wheat, preservatives and lectins can provide remarkable reduction in pain (best seen in migratory/ variable arthritis.)
Treatments are often directed to the neurotransmitters, anxiety, back, knee, gut etc rather than the actual source of the problem. But now as the Covid research confirms microglial sensitization and astrocyte dysfunction, looking back at what causes the inflammatory activation in FMS often provides answers.
The vascular compression syndromes, most prominently the Thoracic Outlet, Jugular Outlet, Internal Jugular Vein obstruction at the venous angles, renal, and iliac vein compression syndromes and median arcuate ligament syndrome are found in all POTS (Postural Orthostatic Compression Syndrome) patients in our studies (over 400 at this point) to varying degrees, and are a common finding in FMS patients (and probably present in all.) Details on these areas are covered in “Assembling the Pieces in POTS.” (43)
There are other compression areas- eg at the distal end of the adductor canal in the thigh, about 12 cm up from the end of the femur, particularly when seated that may produce symptoms, and popliteal vein compression, well described by vascular surgeon Dr David Grosser in: “Popliteal vein compression syndrome the MAIN cause of DVT, unrecognised.”(45) He describes the simplicity of controlling this problem in most people, again with simple changes eg avoiding lying with elevated legs and straight knees, and when standing, unlocking the knees, especially when there is hypermobility.
Treatment
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. Working out the things that are triggering the immune system -the role of activation of the body’s threat receptors (Toll-Like Receptors) and immune response via Mast Cells, affecting microglial and astrocyte function in the nervous system and the symptoms this causes, is critical to understanding and controlling fibromyalgia and its comorbidities.
But like Pandora’s Box, when you open this it can be very complicated with the multiple genetic factors, and various drivers to work out. But each one you do control can improve the quality of life in someone with this immeasurably.
The improvements start with desensitization of the central sensitization, usually achieved through mast cell blockade, and attention to posture and diet while investigations sort out “drivers.” The brain fog, and it’s altered cerebrovascular pressure is a major investigation area, as there appears to be both hypoperfusion and hyperperfusion, with impaired flow in both CSF/lymphatic and venous systems. This area remains a subject of continuing research, although symptoms can be reduced or stopped with the improving physical therapy techniques and attention to lifestyle and especially posture with computers and phones.
The main physical drivers we are seeing are the upper cervical spine and Thoracic Outlet Syndrome. The Internal Jugular Vein obstruction at the stylohyoid and venous angles is becoming increasingly apparent, with the combination of these vascular compression areas seen to increase intracranial vascular pressure. These are usually amenable to postural change, and usually physiotherapy/osteopathic and lymphatic techniques. For many the enemies are phones and laptops with the “forward head” position that has become a major part of our lives. Sustained poor posture has significant impacts on this complex mechanism.
The physical, infective and genetic factors impact on the glymphatic system, the macroscopic system for waste clearance in the brain, using a system of channels around blood vessels, formed by astroglial cells, that are responsible for the defence of the central nervous system. See Glymphatic System (46)
Management remains the same – desensitize the sensitization, work out the drivers, remove the ones we can, and control the inflammatory and autonomic 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.
Where to start management?
High-level acupuncture is also a very useful tool, especially in controlling the inflammatory/ autonomic pathways. In particular, a Japanese style, Kiiko-Matsumoto is usually effective in reducing the autonomic instability. Cymbalta (duloxetine) while hard to use, if tolerated, usually controls the neuropathic pain, and Low Dose Naltrexone (and probably Nigella Sativa) an increasingly useful adjunct, especially in the fatigue component. Tertiary physiotherapy and osteopathy success is dependent on individual mechanical drivers and practitioner skill.
Start with dealing with the obvious:
Is this fibromyalgia?
What co-morbidities are present and can these provide answers to the causes?
What are the underlying causes?
What activated the FMS?
What are the drivers?
Next step
Ensure you are dealing with FMS
Control the mast cell and cytokine response,
Improve the diet and posture is a good starting place wile investigations are underway.
Work out 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,
Acupuncture to control the autonomic instability. Various types of acupuncture vary in effectiveness. At present we are using a Japanese style called “Kiiko Matsumoto” which directly targets the ANS. Good practitioners are able to pick whether a patient is in sympathetic or parasympathetic mode, and tailor treatment accordingly.
Acupuncture
Lai et al (36) demonstrated Toll-like receptor 4 (TLR4) activation produces a harmful sensory input involved in central pain, and that acupuncture has beneficial effects in reducing fibromyalgia pain from modulating the TLR4 response but its connection with TLR4 signaling is still unknown. In addition, they showed that inflammation can activate the TLR4 pathway and provided new possible therapeutic targets for fibromyalgia pain.(88) Other studies show downregulation of inflammatory factors such as interleukins, TNF-α, and IFN-γ, while Liao and Li (37) demonstrated analgesic effect associated with downregulation of the TRPV1 signaling pathway and new potential therapeutic targets for fibromyalgia pain.
In clinic we are currently investigating changing QT Prolongation intervals using Kiiko acupuncture. The QT prolongation can be from medication (shown in QT Interval, (47)) or part of the underlying autonomic process. While still far from being able to publish, we can demonstrate the ability to alter this interval.
Diet Modification
Diet change can be extremely important managing the inflammatory pathways if POTS, Fibromyalgia, dysautonomia and similar conditions. When you eat food the body sees as a threat it releases an inflammatory response with the same pro-inflammatory cytokines being released, as causes the “cytokine storm” in the first place.
This diet seldom addresses all parts of the very complex metabolic processes that are part of these conditions, with the many variations including low histamine, ketogenic etc often needed. Many diets do help, whether FODMAPS, low gluten, elimination, but they seldom provide all the answers.
The emergent theories of astrocyte/glutamate dysfunction in POTS, can sometimes be seen in the clear association of this in autism spectrum, fibromyalgia, ADHD and migraine. Restricting glutamate to already restricted foods may provide extra benefits.
Exorphins
Exorphins are “exogenous opioid peptides” which include gluten exorphin, and can be isolated from various sources eg dairy, and vegetables eg spinach and soy. Research in areas such as autism and schizophrenia have found that genetic mutations can lead to increased absorption in these groups.
Brain opioid peptide systems are known to play an important role in motivation, emotion, attachment behaviour, and responses to stress and pain, the control of food intake and the “rewarding” effects of alcohol and nicotine.
Molecular biologist Dr Valerio Vittone describes: “Soy-derived exorphins may influence brain function and metabolic processes. Similarly, spinach contains opioid peptides that can interact with opioid receptors, affecting both gastrointestinal and neurological functions. The impact of these exorphins can be quite profound, particularly in individuals with certain metabolic or genetic predispositions as we often observe in our problematic patients.”
“Furthermore, nightshades are also very problematic. the potential presence and impact of opioid peptides in nightshade vegetables, such as tomatoes, potatoes, and peppers, are less well-documented however, may represent an intriguing area for further research. These foods contain alkaloids and other compounds that may interact with metabolism and immune function in genotype-specific ways. From my perspective, The interplay between an individual's genotype and their response to food exorphins is a critical factor.
Nutrigenomic approaches, which examine the interaction between diet and genes, are particularly relevant here. Variations in genes related to opioid receptors or metabolic enzymes could significantly alter an individual's response to these dietary peptides.”
Many of the diets available on the internet are simply not validated. The diet in Low Glutamate Diet (31) is from a fact sheet from the Agency for Clinical Innovation, NSW Government. It has been scientifically researched. However, in practical use, I seldom see glutamate as a “stand-alone” problem.
When starting diet change, think about foods that you know you react to- eg dairy, or bread, or gluten, and remove these. If you have migraine, autism, ADHD, fibromyalgia, a 2 week trial of low glutamate, while continuing to avoid the known reactive foods is worth trialling to gauge any response, followed by a formal consultation with our dietician Kelley Bright to progress beyond this diet trial.
Food intolerance and its consequent problems appear to be present in almost all patients with FMS, and many researchers feel this is caused by the activated mast cells as the immune system struggles to contain the perceived threats. The, when you eat food the body sees as a threat, there is again an immune response and cytokines IL2, IL6, IL8 and TNFα (28) are released. Dealing with the intolerance can be 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 dysfunction so these need to be sorted and treated. For example in the MTHFR mutations, these often include vitamin B12, vitamin D, Zinc, and Iodine. Homocysteine has been recognized for years, but “normals” do not correlate with increasing vascular risk, and increasingly elevated homocysteine (over 9) looks to reflect oxidative stress. The research by Dr Valerio Vittone (29)(33) into DNA mutations and the impact from diet has provided a picture of mutations in POTS and Long Covid. It is expected they will be very similar in FMS.
Research from the allergist Dr David Freed implicates lectins as a major dietary factor.(29) 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. The work using DNA has shown the fusion of so many of these pathways and explains why many of the diets tried by patients fail. With the known association of FMS with elevated glutamate potentially adds this pathway into diet modification as well. Sometimes it needs the detailed DNA to put all the pieces together.(31)(32)
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.
What’s next?
Controlling fibromyalgia requires calming this sensitization, controlling the dysautonomia, and sorting out the mechanical, dietary and other lifestyle drivers. Knowing the mast cells are involved provides a starting point, and the histamine pathway needs immediate attention with change to the diet and addition of histamine blockers, usually H1 blockers Telfast or Zyrtec and H2 blockers famotidine, then H4 blockade if needed with Low Dose Naltrexone (LDN), as well as identification of the “drivers” which may be diet, stress, mould, neck pathology, chemical exposure, thoracic outlet syndrome etc.
Non-pharmacological therapies eg CBT can be very helpful in pain management, but patients still report exacerbations with exposure to stress, and only skilled practitioners should attempt this.
Slowly increased exercise consistently has been shown to improve function. It is easy to understand in areas like pelvic congestion as blood flow improves with a break from a desk. In some I advocate a break and gentle mobilizing every 20 minutes.
Recognition of a thoracic outlet/neck combination causing the coathanger pain can improve with attention to posture and better breast support, with avoidance of weight-lifting and similar activities. Breast reduction surgery may be a dramatic but can be effective way of reducing this pain.
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.
It is with tertiary physiotherapy, osteopathy and lymphatic drainage that sustained 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, as they most commonly are driving by the complex mix of Thoracic Outlet Syndrome, scalene pull on the upper cervical spine, and changes in the spine itself, especially loss of lordosis. We have been combining the different physical therapies with increasing levels of success as the therapists gain experience in working together.
Medication:
When there is obvious mast cells involvement, the histamine pathway may benefit from immediate attention with change to the diet and addition of histamine blockers, usually H1 blockers Telfast or Zyrtec and H2 blocker famotidine, then H4 blockade if needed with Low Dose Naltrexone (LDN). I normally use H1 twice daily, more if mast cell activation is marked, and Famotidine 40 mg twice daily, depending on QT intervals and tolerance. This combination has been very effective in managing most Long Covids who are not overly damaged. Increased magnesium is recommended while using famotidine, especially at these higher doses.
The ongoing research into glymphatics has shed light on FMS as well as POTS and long COVID. Professors Marshall-Gradisnik and Smith’s team discovered mutations in an important TRP pathway that affects the function of the glymphatic system and where Low Dose Naltrexone (LDN) improves glymphatic and Natural Killer Cell function. Naltrexone inhibits the 2 critical inflammatory cytokines IL-6 and TNFα, modulating TLR4 on the cell surface, but also has inhibitory effects on endosomal TLRs TLR7/8 and TLR9. It is also considered a Histamine blocker (H4 blocker,) and looks to modulate TLR4. Given the probable impact of elevated glutamate seen in FMS on astrocyte/glymphatic function, and TLR2 signalling appears to be a vital part of the elevated glutamate/astrocyte/glymphatic pathway, there may also be an effect on TLR2 signalling.
As we become more familiar with LDN, I expect we will be able to work out who is most likely to have a major benefit. Although an “off-label” product, it is often very successful in many CFS and FMS patients, particularly with fatigue. Why it is not universally effective, just as mast cell blockade is not always effective needs a closer look at what is happening.
There are similarities between FMS and depression in both genetic and environmental factors. Tricyclic antidepressants, eg amitriptyline and nortriptyline, have long been a drug of first choice. Their success may rely on their modulation of TLR2 and TLR4 signalling (39). More recently it has been found they also modulate T cell and improve Natural Killer Cell function.(40)
Products may reduce pain in fibromyalgia by either increasing levels of inhibitory neurotransmitters (eg, duloxetine) or decreasing levels of excitatory neurotransmitters (eg, pregabalin). (4) In practice, duloxetine, is best in its original form as Cymbalta as the generics consistently have been “underperforming.” Cymbalta is often needed only at 30 mg. It needs to be started at an even lower dosage forcing capsules to be opened and dose reduced then slowly increasing as tolerated. Ceasing Cymbalta can also be difficult. Pregabalin (Lyrica) while recognized as a potential treatment also suffers from even more difficult withdrawal problems. I have also not found it useful in my clinical practice, while Cymbalta is worth the effort of trialling as the level of pain control can be excellent. I do see narcotics being used, which I feel is detrimental to patient well-being, and in patients on high dose narcotics I usually cannot control their symptoms.
Conclusion
Fibromyalgia can be successfully managed. It will wax and wane dependent of environmental factors, especially stress. Management requires a holistic and broad view os each individual patient. While there are many common factors the extent of the co-morbidities often makes understanding and the recovery programs difficult.
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